CN1976908A - Method for preparing 5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]benzamide derivatives with P 2 X 7 inhibiting activity by reaction of the derivative unsubstituted in 4-positi - Google Patents
Method for preparing 5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]benzamide derivatives with P 2 X 7 inhibiting activity by reaction of the derivative unsubstituted in 4-positi Download PDFInfo
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- CN1976908A CN1976908A CNA2005800218405A CN200580021840A CN1976908A CN 1976908 A CN1976908 A CN 1976908A CN A2005800218405 A CNA2005800218405 A CN A2005800218405A CN 200580021840 A CN200580021840 A CN 200580021840A CN 1976908 A CN1976908 A CN 1976908A
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Abstract
The present invention relates to methods of preparing compounds of formula (I), R<SUP>7</SUP> is -CH<SUB>2</SUB>-C(R<SUP>10</SUP>R<SUP>11</SUP>)-OH, wherein R<SUP>10</SUP> and R<SUP>11</SUP> are independently selected from the group consisting of: hydrogen, phenyl, and (C<SUB>1</SUB>-C<SUB>6</SUB>)alkyl optionally substituted with one to three halos, hydroxy, -CN, (C<SUB>1</SUB>-C<SUB>6</SUB>)alkoxy-,((C<SUB>1</SUB>-C<SUB>6</SUB>)alkyl)<SUB>n</SUB>-N-,(C<SUB>1</SUB>-C<SUB>6</SUB>)alkyl-(C=O)-,(C<SUB>3</SUB>-C<SUB>8</SUB>)cycloalkyl-(C=O)-, 5 or 6-membered heterocycloalkyl-(C=O)-,phenyl-(C=O)-,naphthyl-(C=O)-,5- or 6-membered heteroaryl-(C=O)-,(C<SUB>1</SUB>-C<SUB>6</SUB>)alkyl-(C=O)O-,(C<SUB>1</SUB>-C<SUB>6</SUB>)alkyl-O(C=O)-,(C<SUB>3</SUB>-C<SUB>8</SUB>)cycloalkyl, phenyl, naphthyl, 5 or 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; or a pharmaceutically acceptable salt thereof, wherein R<SUP>1</SUP>, R<SUP>2</SUP> and R<SUP>4</SUP> have any of the values as defined in the specification. Wherein said method comprises reacting a compound of formula (II) with a compound of formula (VIII) in the presence of at least one Lewis acid. The compounds are useful as agents in the treatment of diseases, including inflammatory diseases such as rheumatoid arthritis. Also provided are compositions of crystalline 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2R-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide comprising less than 2.5% residual organic solvent, and methods for preparing said compositions. Further provided are methods for crystallizing 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2R-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.
Description
The related application of cross reference
The application requires the right of priority of the U.S. temporary patent application submitted on June 29th, 2004 number 60/583,813.
Background technology
P2X
7Purinergic receptor (being called the P2Z acceptor in the past) is a kind of ligand-gated ion channel, is present in the multiple cell type, and mainly be the cell type of known participation inflammatory/immunologic process, specifically, scavenger cell, mastocyte and lymphocyte (T and B).Extracellular Nucleotide, particularly Triphosaden is to P2X
7The activation of acceptor can cause interleukin-1 ' beta ' (IL-1 β) to discharge and giant cells forms (scavenger cell/microgliacyte), threshing (mastocyte) and breed (T cell), apoptosis and L-selection albumen come off (lymphocyte).P2X
7Acceptor also is positioned on antigen presenting cell (APC), keratinocyte, sialisterium cystencyte (parotid gland cell), liver cell and the mesangial cell.
P2X
7Antagonist is known in the art, for example at international monopoly open WO 01/46200, WO 01/42194, WO 01/44213, WO 99/29660, WO 00/61569, WO 99/29661, WO 99/29686, WO 00/71529 and WO 01/44170, and described in the WO 2003/042191 those.
At a lot of publications open WO 97/22600, EP 138 of international monopoly for example, 527, paraphenylene terephthalamide class, heteroaryl amides class and anti-amides are described among WO00/71509, WO 98/28269, WO 99/17777 and the WO 01/58883, do not suppress P2X but describe it
7The purposes of acceptor.
Through identifying P2X
7The antagonist of acceptor can be used for the treatment of the people disease (referring to, people such as Alcaraz for example, (2003) Bioorg Med chem Lett.13 (22): 4043-4046; People such as Baxter (2003) Bioorg Med Chem Lett.13 (22): 4047-4050).The inhibition P2X that people need other composition and preparation to use as medicament
7The method of the compound of acceptor.
Summary of the invention
On the one hand, the invention provides the compound of preparation general formula I or the method for its pharmacologically acceptable salts,
R wherein
1Be (C
1-C
6) alkyl, optional by (C
3-C
8) cycloalkyl, phenyl, naphthyl, 5 or 6-unit's Heterocyclylalkyl or 5-or 6-unit heteroaryl replace each described (C wherein
1-C
6) alkyl, (C
3-C
8) cycloalkyl, phenyl, naphthyl, 5-or 6-unit's Heterocyclylalkyl or 5-or 6-unit heteroaryl is optional is independently selected from hydroxyl, halogen, CN-, (C by 1 to 3
1-C
6) alkyl, HO (C
1-C
6) alkyl, (C
1-C
6) alkyl-NH (C=O)-, NH
2(C=O)-, (C
1-C
6) alkoxyl group or (C
3-C
8) group of cycloalkyl replaces;
R
2Be hydrogen, halogen ,-CN or (C
1-C
6) alkyl, wherein said (C
1-C
6) alkyl optional by 1 to 3 be independently selected from halogen, hydroxyl, amino ,-CN, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-CF
3, CF
3O-, (C
1-C
6) alkyl-NH-, [(C
1-C
6) alkyl]
2-N-, (C
1-C
6) alkyl-S-, (C
1-C
6) alkyl-(S=O)-, (C
1-C
6) alkyl-(SO
2)-, (C
1-C
6) alkyl-O-(C=O)-, formyl radical, (C
1-C
6) alkyl-(C=O)-and (C
3-C
6) group of cycloalkyl replaces;
R wherein
4Be independently selected from hydrogen, halogen, hydroxyl ,-CN, HO-(C
1-C
6) alkyl, optional by the (C of 1-3 fluorine replacement
1-C
6) alkyl, optional by the (C of 1-3 fluorine replacement
1-C
6) alkoxyl group, HO
2C-, (C
1-C
6) alkyl-O-(C=O)-, R
5R
6N (O
2S)-, (C
1-C
6) alkyl-(O
2S)-NH-, (C
1-C
6) alkyl-O
2S-[(C
1-C
6) alkyl-N]-, R
5R
6N (C=O)-, R
5R
6N (CH
2)
m-, phenyl, naphthyl, (C
3-C
8) cycloalkyl, 5-or 6-unit heteroaryl, 5-or 6-unit Heterocyclylalkyl, phenyl-O-, naphthyl-O-, (C
3-C
8) cycloalkyl-O-, 5-or 6-unit's heteroaryloxy and 5 or Heterocyclylalkyl-the O-of 6-unit; With
R
7Be-CH
2-C (R
10R
11)-OH, wherein R
10And R
11Be independently selected from:
Hydrogen, phenyl and the optional (C that is replaced by 1-3 halogen
1-C
6) alkyl, hydroxyl ,-CN, (C
1-C
6) alkoxyl group-, ((C
1-C
6) alkyl)
n-N-, (C
1-C
6) alkyl-(C=O)-, (C
3-C
8) cycloalkyl-(C=O)-, 5 or 6-unit Heterocyclylalkyl-(C=O)-, phenyl-(C=O)-, naphthyl-(C=O)-, 5-or 6-unit heteroaryl-(C=O)-, (C
1-C
6) alkyl-(C=O) O-, (C
1-C
6) alkyl-O (C=O)-, (C
3-C
8) cycloalkyl, phenyl, naphthyl, 5 or 6-unit's Heterocyclylalkyl and 5-or 6-unit heteroaryl;
R
5And R
6Be selected from hydrogen, (C independently of one another
1-C
6) alkyl, HO-(C
2-C
6) alkyl and (C
3-C
8) cycloalkyl, perhaps R
5And R
6Can choose wantonly with nitrogen-atoms and link together formation 5-or 6-unit Heterocyclylalkyl;
N is 1 or 2; With
M is 1 or 2;
Wherein said method comprises the compound with general formula I I
Compound with general formula VIII
Reaction in the presence of at least a Lewis acid.In some embodiments, this Lewis acid is an inorganic lewis acid.In other embodiments, this Lewis acid is a boron trifluoride diethyl ether compound.In other embodiments, this Lewis acid is Al
2O
3, Ti (O-Pr
i)
4, LiClO
4, or Zn (OAc)
2And in other embodiments, this Lewis acid is selected from (a) Eu (OTf)
3, Dy (OTf)
3, Ho (OTf)
3, Er (OTf)
3, Lu (OTf)
3, Yb (OTf)
3, Nd (OTf)
3, Gd (OTf)
3, Lu (OTf)
3, La (OTf)
3, Pr (OTf)
3, Tm (OTf)
3, Sc (OTf)
3, Sm (OTf)
3, AgOTf or Y (OTf)
3(b) AlCl
3, AlI
3, AlF
3, AlBr
3, AsCl
3, AsI
3, AsF
3, AsBr
3, BCl
3, BBr
3, BI
3, BF
3, FeCl
3, FeBr
3, FeI
3, FeF
3, FeCl
2, FeBr
2, FeI
2, FeF
2, GaCl
3, GaI
3, GaF
3, GaBr
3, MgCl
2, MgI
2, MgF
2, MgBr
2, NbCl
5, SbCl
3, SbI
3, SbF
3, SbBr
3, SbCl
5, SbI
5, SbF
5, SbBr
5, SnCl
2, SnI
2, SnF
2, SnBr
2, SnCl
4, SnI
4, SnF
4, SnBr
4, TiBr
4, TiCl
2, TiCl
3, TiCl
4, TiF
3, TiF
4, TiI
4, ZnCl
2, ZnI
2, ZnF
2, or ZnBr
2(c) BF
3BCl
3SMe
2, BI
3SMe
2, BF
3SMe
2, BBr
3SMe
2, BF
3OEt
2, Et
2AlCl, EtAlCl
2, MgCl
2OEt
2, MgI
2OEt
2, MgF
2OEt
2, MgBr
2OEt
2, Et
2AlCl, EtAlCl
2, or Zn (OAc)
2(d) (CH
3CO
2)
2Co, CoBr
2, CoCl
2, CoF
2, CoI
2, Co (NO
3)
2, trifluoromethanesulfonic acid cobalt (II), toluenesulphonic acids cobalt (II), (CH
3CO
2)
2Cu, CuBr
2, CuCl
2, CuF
2, CuI
2, Cu (NO
3)
2, copper trifluoromethanesulfcomposite (II), toluenesulphonic acids copper (II), (CH
3CO
2)
2Ni, NiBr
2, NiCl
2, NiF
2, NiI
2, Ni (NO
3)
2, trifluoromethanesulfonic acid nickel (II) or toluenesulphonic acids nickel (II).In other embodiments, this Lewis acid is a silica gel.In some embodiments, this is reflected at N, carries out in dinethylformamide, N,N-dimethylacetamide or N-Methyl pyrrolidone or their mixture.In specific embodiment, the compound of per 1 mole general formula I I exists with compound less than 6 moles general formula VIII; The compound of per 1 mole general formula I I exists with compound less than 5 moles general formula VIII; The compound of the general formula VIII of the compound of perhaps per 1 mole general formula I I and 1 to 2 mole exists.In other embodiments, the compound of general formula VIII is (R)-(-)-glycidyl methyl ether.In other embodiments, the compound of general formula I I is 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-N-(1-hydroxyl-suberyl methyl)-benzamide.In specific embodiment, the compound of general formula I is 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide.Preparation 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 is provided in certain embodiments, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-method of benzamide, wherein said method comprises 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-N-(1-hydroxyl-suberyl methyl)-benzamide with (R)-(-)-the glycidyl methyl ether reacts in the presence of silica gel, wherein this is reflected at N, dinethylformamide, N,N-dimethylacetamide, or carry out in N-Methyl pyrrolidone or their mixture.This method also comprises following embodiments, wherein R
1Be (C
1-C
4) alkyl, optional by (C
3-C
8) cycloalkyl substituted; Wherein said (C
1-C
4) alkyl or (C
3-C
8) cycloalkyl is optional is independently selected from hydroxyl, halogen, CN-, (C by 1 to 3
1-C
6) alkyl, HO (C
1-C
6) alkyl, (C
1-C
6) alkyl-NH (C=O)-, NH
2(C=O)-, (C
1-C
6) alkoxyl group or (C
3-C
8) group of cycloalkyl replaces.In some embodiments, R
2Can be chlorine, methyl or ethyl.In other embodiments, R
4Be hydrogen and R
7Be-CH
2-C (R
10R
11)-OH, wherein R
10And R
11Can be independently selected from: hydrogen and optional by (C
1-C
6) alkoxyl group-or-(C that OH replaces
1-C
6) alkyl.In other embodiments, R
7Can be selected from:
On the other hand, the invention provides 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-composition of benzamide, comprise: crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide; With less than 2.5% residual organic solvent.In some embodiments, said composition comprises the residual organic solvent less than 2.0% (w/w); 0.1 residual organic solvent to 2.0% (w/w); 0.1 residual organic solvent to 0.5% (w/w); Or the residual organic solvent of 0.05 to 0.5% (w/w).In some embodiments, this residual organic solvent is an acetone.In specific embodiment, by determine with dsc method, the initial fusing point that said composition has is between 108 ℃ ± 0.5 to 112 ℃ ± 0.5.In specific embodiment, by determine with dsc method, the initial fusing point that said composition has is between 110 ℃ ± 0.5 to 112 ℃ ± 0.5.In some embodiments, use CuK
αThe X-ray powder diffraction that radiation detection, said composition have comprises following 2-θ value ± 0.2:8.1,16.4,19.7,21.2,22.2 and 27.1.In other embodiments, use CuK
αThe X-ray powder diffraction that radiation detection, said composition have comprises following 2-θ value ± 0.2:8.1,11.7,14.9,16.4,18.3,19.7,21.2,21.6,22.2,22.6 and 27.1.In other embodiment, use CuK
αThe X-ray powder diffraction that radiation detection, said composition have comprises following 2-θ value ± 0.2:7.8,8.1,10.5,11.7,13.2,13.7,14.3,14.9,15.6,16.4,17.3,17.7,18.3,18.9,19.1,19.7,20.3,20.9,21.2,21.6,22.2,22.6,22.8,23.3,23.9,24.3,24.6,25.1,25.9,26.2,27.1,27.6,28.2,28.7,28.8,29.4,30.0,30.3,30.9,31.1,31.9,33.4,33.8,34.3,35.2 and 37.1.In some embodiments, the also available solid-state 13C nucleus magnetic resonance of said composition characterizes, and comprises following chemical shift difference between minimum ppm resonance and other resonance: 150.6,137.6,119.5 and 54.8.In some embodiments, said composition is with solid-state
13The C nucleus magnetic resonance characterizes, and comprises following chemical shift difference between minimum ppm resonance and other resonance: 150.6,137.6,130.1,129.2,121.4,120.5,119.5,117.7,113,112.7,111.6,110.3,109.5,107.3,106,54.8,53.9,47.7,45.9,41.2,38,34.2,31.2,24.7,20.8,19.0,18.1,17.4,12.2,10.1,4.0,3.5 and 1.2.In some embodiments, said composition characterizes with solid-state 13C nucleus magnetic resonance, comprises the following chemical shift of representing with ppm: 169.8,156.8,138.7 and 74.0.In some embodiments, said composition is with solid-state
13The C nucleus magnetic resonance characterizes, and comprises the following chemical shift of representing with ppm: 169.8,156.8,149.3,148.4,140.6,139.7,138.7,136.9,132.2,131.9,130.8,129.5,128.7,126.5,125.2,74.0,73.1,66.9,65.1,60.4,57.2,53.4,50.4,43.9,40.0,38.2,37.3,36.6,31.4,29.3,23.2,22.7,20.4 and 19.2.
On the other hand, the invention provides and prepare 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 that comprises less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-method for compositions of benzamide, comprise: comprising 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-normal heptane sneaked in the acetone soln of benzamide, to produce 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal of benzamide; With separate 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 that comprises less than 2.5% (w/w) residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-the benzamide crystal.In some embodiments, separate and comprise this crystal of filtration from solvent, and dry this crystal.In other embodiment, said composition contains the residual organic solvent less than 2.0% (w/w).In other embodiment, said composition contains the residual organic solvent of 0.1 to 2.0% (w/w).And in other embodiments, said composition contains the residual organic solvent of 0.1 to 0.5% (w/w).This residual organic solvent can be an acetone.In specific embodiment, by determine with dsc method, the initial fusing point that said composition has is between 108 ℃ ± 0.5 to 112 ℃ ± 0.5.In specific embodiment, by determine with dsc method, the initial fusing point that said composition has is between 110 ℃ ± 0.5 to 112 ℃ ± 0.5.In some embodiments, use CuK
αThe X-ray powder diffraction that radiation detection, said composition have comprises following 2-θ value ± 0.2:8.1,16.4,19.7,21.2,22.2 and 27.1.In other embodiments, use CuK
αThe X-ray powder diffraction that radiation detection, said composition have comprises following 2-θ value ± 0.2:8.1,11.7,14.9,16.4,18.3,19.7,21.2,21.6,22.2,22.6 and 27.1.In other embodiment, use CuK
αThe X-ray powder diffraction that radiation detection, said composition have comprises following 2-θ value ± 0.2:7.8,8.1,10.5,11.7,13.2,13.7,14.3,14.9,15.6,16.4,17.3,17.7,18.3,18.9,19.1,19.7,20.3,20.9,21.2,21.6,22.2,22.6,22.8,23.3,23.9,24.3,24.6,25.1,25.9,26.2,27.1,27.6,28.2,28.7,28.8,29.4,30.0,30.3,30.9,31.1,31.9,33.4,33.8,34.3,35.2 and 37.1.In some embodiments, said composition is also available solid-state
13The C nucleus magnetic resonance characterizes, and comprises following chemical shift difference between minimum ppm resonance and other resonance: 150.6,137.6,119.5 and 54.8.In some embodiments, said composition characterizes with solid-state 13C nucleus magnetic resonance, comprises following chemical shift difference between minimum ppm resonance and other resonance: 150.6,137.6,130.1,129.2,121.4,120.5,119.5,117.7,113,112.7,111.6,110.3,109.5,107.3,106,54.8,53.9,47.7,45.9,41.2,38,34.2,31.2,24.7,20.8,19.0,18.1,17.4,12.2,10.1,4.0,3.5 and 1.2.In some embodiments, said composition is with solid-state
13The C nucleus magnetic resonance characterizes, and comprises the following chemical shift of representing with ppm: 169.8,156.8,138.7 and 74.0.In some embodiments, said composition is with solid-state
13The C nucleus magnetic resonance characterizes, and comprises the following chemical shift of representing with ppm: 169.8,156.8,149.3,148.4,140.6,139.7,138.7,136.9,132.2,131.9,130.8,129.5,128.7,126.5,125.2,74.0,73.1,66.9,65.1,60.4,57.2,53.4,50.4,43.9,40.0,38.2,37.3,36.6,31.4,29.3,23.2,22.7,20.4 and 19.2.
On the other hand, the present invention relates to prepare crystal 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 that comprises less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-method for compositions of benzamide, comprise: comprising 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-sneak into normal heptane in the acetone soln of benzamide, produce 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal of benzamide; With separate 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 that comprises less than 2.5% (w/w) residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal of benzamide.In some embodiments, this method comprises filters crystal from solvent, and dry this crystal.In some embodiments, said composition contains the residual organic solvent less than 2.0% (w/w); 0.1 residual organic solvent to 2.0% (w/w); Or the residual organic solvent of 0.1 to 0.5% (w/w).
On the other hand, the invention provides treatment and suffer from the patient's of disease method, described disease is selected from rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, arthritic psoriasis, psoriasis, inflammatory diseases and autoimmune disorder, this method comprises: the administering therapeutic significant quantity comprise crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-composition of benzamide, wherein this compound comprises the residual organic solvent less than 2.5%.In some embodiments, this disease is a rheumatoid arthritis.This disease also can be the disease of IL-1 mediation.As defined herein, " disease of IL-1 mediation " includes but not limited to be selected from following disease or illness: sacroiliitis (comprises arthritic psoriasis, Reiter syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and acute synovitis), inflammatory bowel, Crohn disease, wind-puff, adult respiratory distress syndrome, adult respiratory distress syndrome, asthma segmental bronchus chronic obstructive pulmonary disease, chronic pulmonary inflammation disease, silicosis, sarcoidosis of lung, atopic reaction, the allergic contact allergy, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulcer, restenosis, periodontopathy, epidermolysis bullosa, osteoporosis, bone-resorbing disease, prosthetic joint implants is lax, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, apoplexy, cerebral ischemia, head trauma, neurotrauma, Spinal injury, neurodegenerative disease, alzheimer's disease, Parkinson's disease, migraine, depressed, peripheral neuropathy, pain, cerebral amyloid angiopathy, intelligence development or cognitive the enhancing, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis takes place, corneal injury, macular degeneration, corneal scar forms, scleritis, unusual wound healing, burn, autoimmune disorder, Huntington's disease, diabetes, AIDS, emaciation, septicemia, septic shock, endotoxin shock, the conjunctivitis shock, gram positive sepsis, toxic shock syndrome, cerebral malaria, heart and kidney reperfusion injury, thrombosis, glomerulonephritis, graft-vs-host reaction, allograft rejection, organ transplantation toxicity, ulcerative colitis, or muscle deterioration.
On the other hand, the invention provides pharmaceutical composition, comprise: the treatment significant quantity comprise crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide, mix with at least a pharmaceutically acceptable carrier.
On the other hand, the invention provides a kind of method of pharmaceutical compositions, comprise: will comprise crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide mixes with at least a pharmaceutically acceptable carrier.
On the other hand, the invention provides 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-composition of benzamide, comprise: crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide; By determine with dsc method, its initial fusing point that has is between 108 ℃ ± 0.5 to 112 ℃ ± 0.5.In some embodiments, by determine with dsc method, the initial fusing point that said composition has is between 110 ℃ ± 0.5 to 112 ℃ ± 0.5.
On the other hand, the invention provides the method for a kind of pharmaceutical composition of preparation, comprise: will pass through determine with dsc method, 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 of the initial fusing point that has between 108 ℃ ± 0.5 to 112 ℃ ± 0.5,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide mixes with at least a pharmaceutically acceptable carrier.
On the other hand, the invention provides a kind of preparation crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-method of benzamide, comprise: crystallization 2-chloro-N-(1-hydroxyl-suberyl methyl) from acetone, diisopropyl ether, n-butyl acetate, normal heptane, methyl alcohol, tetrahydrofuran (THF) or methyl ethyl ketone-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide.
Compound of the present invention comprises all steric isomers (for example cis and trans-isomer(ide)) and all optically active isomers (for example, the corresponding body of R and S) of compound of Formula I, and the racemize of these isomer, diastereomer and other mixtures.
Compound of the present invention and salt can exist with some kinds of tautomeric forms, comprise the form of enol and imines and form and the geometrical isomer and their mixture of ketone and enamine.All these tautomeric forms all comprise within the scope of the invention.Tautomer mixture as tautomeric form in solution exists.In solid form, common a kind of tautomer is preponderated.Although can describe a kind of tautomer, the present invention includes all tautomers of this compound.An example of tautomeric structure is following one group:
Those skilled in the art will appreciate that this group also can plot its tautomer:
The present invention also comprises atropisomer.Atropisomer is meant the compound of the general formula I that can be separated into the limited isomer of spin.
Compound of the present invention can comprise two keys of alkene sample.When having such key, compound of the present invention exists with cis and transconfiguration with their mixture.
Definition
Term " alkyl group " or " alkyl " comprise the carbochain group of straight chain and side chain.Term " alkylidene group " is meant the diradical of the alkane of unsubstituted or replacement.For example, " C
2-6Alkyl " be alkyl with 2 to 6 carbon atoms.C
2-C
6The example of straight chained alkyl includes but not limited to, ethyl, n-propyl, normal-butyl, n-pentyl and n-hexyl.The example of branched-chain alkyl includes but not limited to, sec.-propyl, the tertiary butyl, isobutyl-or the like.The example of alkylidene group includes but not limited to-CH
2-,-CH
2-CH
2-,-CH
2-CH (CH
3)-CH
2-and-(CH
2)
1-3Alkylidene group can be replaced about the substituting group in the alkyl by following.
The term alkyl comprises " unsubstituted alkyl " and " alkyl of replacement ", and wherein the latter is meant that the hydrogen on one or more carbon on the hydrocarbon main chain is substituted the moieties that base replaces.These substituting groups are independently selected from: halogen, I, Br, Cl, F;-OH ,-COOH, trifluoromethyl ,-NH
2,-OCF
3, and O-C
1-C
3
Therefore, the typical alkyl that replaces is 2,3-dichloro amyl group, 3-hydroxyl-5-carboxyl hexyl, 2-aminopropyl, pentachloro-butyl, trifluoromethyl, methoxyethyl, 3-hydroxyl amyl group, 4-chlorobutyl, 1,2-dimethyl-propyl group and pentafluoroethyl group.
" halogen " comprises fluorine, chlorine, bromine and iodine.
Term " C
3-C
8Cycloalkyl " be meant cycloalkyl with 3 to 8 carbon.Therefore, term " C
3-C
8Cycloalkyl " comprise the monocycle alkyl with 3 to 8 carbon and the bicyclic alkyl that comprises 7 or 8 carbon." C
3-C
8Cycloalkyl " example include but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and two ring [2.2.1] heptyl; Cycloalkyl can be chosen wantonly and comprise 1 or 2 two key (being cycloalkenyl group), includes but not limited to cyclopentenyl, cyclohexenyl and cycloheptenyl." C
3-C
8Cycloalkyl " can be independently selected from C by 1 or 2
1-C
3Alkyl (for example methyl) and-O-C
1-C
3The group of alkyl (for example, methoxyl group) replaces.The example of the cycloalkyl that replaces includes but not limited to methyl-cyclopropyl, dimethyl-cyclohexyl, 2-methyl-cyclohexyl base, 3-methyl-cyclohexyl base, 3,5-dimethyl-cyclohexyl and 4-methyl-cyclohexyl base.
" 5-unit Heterocyclylalkyl " is stable 5-unit monocycle alkyl, and it has 2 to 4 carbon atoms and 1 to 3 heteroatoms, is selected from: 10; 1S; 1N; 2N; 3N; 1S and 1N; 1S and 2N; 10 and 1N; And 10 and 2N.The illustrative example of stable 5-unit Heterocyclylalkyl comprise tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, imidazolidyl, _ oxazolidinyl, imidazolinyl, different _ oxazolidinyl, pyrrolidyl, 2-pyrrolinyl and 3-pyrrolinyl.
" 6-unit Heterocyclylalkyl " is stable 6-unit monocycle alkyl, and it has 3 to 5 carbon atoms and 1 to 3 heteroatoms, is selected from: 10; 20; 1S; 2S; 1N; 2N; 3N; 1S, 10 and 1N; 1S and 1N; 1S and 2N; 1S and 10; 1S and 20; 10 and 1N; And 10 and 2N.The illustrative example of stable 6-unit Heterocyclylalkyl comprises THP trtrahydropyranyl, dihydro pyranyl, dioxacyclohexyl, 1,3-dioxane amyl group, 1,4-dithia cyclohexyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidyl, 2H-pyranyl, 4H-pyranyl, pyrazolidyl, pyrazolinyl, 1,2,3,6-tetrahydro pyridyl, tetrahydrochysene sulfo-pyranyl, 1,1-dioxy-six hydrogen-1 λ
6-sulfo-pyranyl, 1,1-dioxy-1 λ
6-thio-morpholinyl, thio-morpholinyl, thiophene _ alkyl and trithio piperidyl.
Above-mentioned Heterocyclylalkyl can be that C-connects or N-connects.For example, piperidyl can be piperidines-1-base (N-connection) or piperidin-4-yl (C-connection).
Term " 5 or 6 yuan of Heterocyclylalkyls " be included in the 5 yuan of rings (for example 2-pyrrolinyl, 3-pyrrolinyl etc.) that comprise a carbon-to-carbon or the two keys of carbon-nitrogen in the ring and in ring, comprise a carbon-to-carbon or 6 yuan of rings of carbon-nitrogen pair keys (for example, dihydro-2H-pyranyl, 1,2,3,4 tetrahydropyridines, 3,4-dihydro-2H-[1,4] _ piperazine etc.).When may the time, " 5 or 6 yuan of Heterocyclylalkyls " can be by for example at above-mentioned C
3-C
8The group of enumerating in the cycloalkyl replaces.
Term " phenyl " is meant the phenyl that does not replace or replace.Phenyl can be independently selected from C by 1 to 3
1-C
3Alkyl ,-O-C
1-C
3Alkyl ,-OCF
3, halogen and C
5-C
6The substituting group of cycloalkyl replaces.
The typical phenyl that replaces includes but not limited to, the 3-chloro-phenyl-, 2, the 6-dibromo phenyl, 2,4,6-tribromo phenyl, 2, the 6-dichlorophenyl, the 4-trifluoromethyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,5-dimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3-methoxyl group-phenyl, 4-methoxyl group-phenyl, 3,5-two fluoro-phenyl, 4-chloro-phenyl, 3-trifluoromethyl-phenyl, 3,5-two chloro-phenyl, 2-methoxyl group-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 4-chloro-2-trifluoromethyl-phenyl or the like.
" 5-unit heteroaryl " is stable 5-unit monocyclic aromatic rings base, and it has 1 to 4 carbon atom and 1 to 4 heteroatoms, is selected from: 10; 1S; 1N; 2N; 3N; 4N; 1S and 1N; 1S and 2N; 10 and 1N; And 10 and 2N.The illustrative example of stable 5-unit heteroaryl includes but not limited to, furyl, 2-furyl, 3-furyl, imidazolyl, different _ the azoles base, isothiazolyl, _ di azoly, _ azoles base, pyridyl, 2-, 3-, or 4-pyridyl, pyrimidyl, 2-, 4-, or 5-pyrimidyl, pyrazolyl, pyrryl, 2-or 3-pyrryl, pyrazinyl, pyridazinyl, 3-or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3-thienyl, tetrazyl, thiazolyl, thiadiazolyl group, triazinyl and triazolyl.
" 6-unit heteroaryl " is stable 6-unit monocyclic aromatic rings base, and it has 3 to 5 carbon atoms and 1 to 3 heteroatoms, is selected from: 1N; 2N; And 3N.The illustrative example of stable 6-unit heteroaryl comprises pyridine-2-base, pyridin-4-yl, pyrimidine-2-base, pyridazine-4-base and pyrazine-2-base.
5-or 6-unit heteroaryl can be chosen wantonly by 1 to 3 and be independently selected from C
1-C
3Alkyl ,-O-C
1-C
3Alkyl ,-OCF
3, and the substituting group of halogen replace.
" naphthyl " is meant and replaces or unsubstituted naphthyl.Naphthyl can be independently selected from C by 1 to 4
1-C
3Alkyl ,-O-C
1-C
3Alkyl ,-OCF
3, halogen and C
5-C
6The substituting group of cycloalkyl replaces.
Description of drawings
Accompanying drawing 1
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-the dsc calorifics collection of illustrative plates of benzamide (embodiment 4, sample D).
Accompanying drawing 2
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide (embodiment 4, sample D) solid-state
13The C-NMR spectrum.
Accompanying drawing 3
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-powder x-ray diffraction (PXRD) spectrum of benzamide (embodiment 4, sample D).
Detailed Description Of The Invention
I. introduce
The present invention relates to the preparation of compound He the acceptable salt of its pharmacy of general formula I, described compound can be used as medicament and is used for the treatment of disease, comprises for example rheumatoid arthritis of inflammatory disease. The crystal 2 that comprises less than 2.5% residual organic solvent-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3 also is provided, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-composition of benzamide, and prepare the method for described composition. Provide in addition crystallization 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-method of benzamide.
II. the method for preparing compound
The compound of preparation general formula I, comprise and use synthetic method known in the art, the synthetic method of summarizing in the following listed scheme, and in U.S. Patent Application Serial Number 10/748, method described in 340 is incorporated herein this patent integral body by reference at this.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 1 relates to the preparation of the compound of general formula I. The compound of general formula I (for example, 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide) can be by the compound of general formula I I (for example, 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-and N-(1-hydroxyl-suberyl methyl)-benzamide) preparation, with the substituted epoxy ethane of itself and suitable general formula VIII (for example comprise, (R)-(-)-and the glycidyl methyl ether) reaction in the presence of the lewis acid of catalytically effective amount and polar solvent, described polar solvent includes but not limited to DMF, DMA or 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO) and oxolane. Above-mentioned reaction can be carried out 2 to 72 hours under 0 ℃ to 100 ℃ of temperature ranges, and wherein preferred condition is reaction 24 hours in dimethyl formamide under 60 ℃. In some embodiments, this reaction can be finished in inert gas atmosphere (for example, nitrogen) with atent solvent (for example, anhydrous solvent) under the inert reaction condition. Lewis acidic example comprises having formula M XtCompound, wherein M is selected from Al, As, B, Fe, Fe, Ga, Mg, Nb, Sb, Sn, Ti and Zn. X is halogen, is selected from Cl, I, F and Br. It will be recognized by those skilled in the art that according to the valence state of M, t is 2 to 5 integer. Formula M XtThe example of compound include but not limited to: AlCl3、AlI
3、AlF
3、AlBr
3、
AsCl
3、AsI
3、AsF
3、AsBr
3、BCl
3、BBr
3、BI
3、BF
3、FeCl
3、FeBr
3、FeI
3、
FeF
3、FeCl
2、FeBr
2、FeI
2、FeF
2、GaCl
3、GaI
3、GaF
3、GaBr
3、MgCl
2、
MgI
2、MgF
2、MgBr
2、NbCl
5、SbCl
3、SbI
3、SbF
3、SbBr
3、SbCl
5、SbI
5、
SbF
5、SbBr
5、SnCl
2、SnI
2、SnF
2、SnBr
2、SnCl
4、SnI
4、SnF
4、SnBr
4、
TiBr
4、TiCl
2、TiCl
3、TiCl
4、TiF
3、TiF
4、TiI
4、ZnCl
2、ZnI
2、ZnF
2, and ZnBr2 In addition, for example can use lewis acid, Al2O
3、BF
3BCl
3·SMe
2、
BI
3·SMe
2、BF
3·SMe
2、BBr
3·SMe
2、BF
3·OEt
2、Et
2AlCl、EtAlCl
2、MgCl
2·OEt
2、
MgI
2·OEt
2、MgF
2·OEt
2、MgBr
2·OEt
2、Et
2AlCl、EtAlCl
2、LiClO
4(lithium perchlorate), Ti (O-Pri)
4(four isopropyl titanium oxide) and Zn (OAc)2 In another embodiment, cobalt (II), copper (II) and nickel (II) salt, for example (CH3CO
2)
2Co、CoBr
2、
CoCl
2、CoF
2、CoI
2、Co(NO
3)
2, TFMS cobalt (II), toluenesulfonic acid cobalt (II), (CH3CO
2)
2Cu、CuBr
2、CuCl
2、CuF
2、CuI
2、Cu(NO
3)
2, copper trifluoromethanesulfcomposite (II), toluenesulfonic acid copper (II), (CH3CO
2)
2Ni、NiBr
2、NiCl
2、NiF
2、NiI
2、Ni(NO
3)
2, TFMS nickel (II) and toluenesulfonic acid nickel (II) can be used for the reaction of VIII and II. Monoalkyl halogenation boron, dialkyl group halogenation boron, single aryl halogenation boron and diaryl halogenation boron also can be used as lewis acid and use. The rare earth metal salt of TFMS is Eu (OTf) for example3、
Dy(OTf)
3、Ho(OTf)
3、Er(OTf)
3、Lu(OTf)
3、Yb(OTf)
3、Nd(OTf)
3、Gd(OTf)
3、
Lu(OTf)
3、La(OTf)
3、Pr(OTf)
3、Tm(OTf)
3、Sc(OTf)
3、Sm(OTf)
3、AgOTf、
Y(OTf)
3, and its fluoropolymer resin (polystyrene resin of TFMS scandium for example; PS-Sc (OTf)2) can in the solution of for example 1 part of water and 4 to 9 parts of oxolanes, use. In addition, the silica gel (CAS 112926-00-8) that in this reaction, can use silica gel for example in column chromatography, to use, preferred size is the 80-500 order. In some embodiments, this lewis acid is silica gel, and reaction is for example carried out in DMF, DMA or 1-METHYLPYRROLIDONE or their mixture at solvent. Above-mentioned lewis acid also comprises heteropoly acid or their salt, zeolite-type molecular sieve, Louis's conjugate acid-type super acid or lewis acid (AlCl for example3、BF
3, or XF5(X=P, As, Sb or Bi))-oxide or the molecular sieve processed and be loaded with porous inorganic carrier (for example C, the SiO of activation2、
Al
2O
3、MgO、TiO
2, natural or synthetic alumino-silicate-type zeolite).
Scheme 2 relates to the preparation of the compound of general formula I I. The compound of general formula I I can be prepared by the compound of general formula I X (for example, 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-benzoic acid), comprises the compound H with itself and general formula X IV2N-R
1(for example 1-amino methyl-suberol HCl) reacts in the presence of coupling agent and alkali, wherein said coupling agent and alkali are in aprotic solvent, described coupling agent is 1-[3-(dimethylamino) propyl group for example]-3-ethyl carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 1,1 '-carbonyl dimidazoles (CDI), described alkali for example is dimethyl aminopyridine (DMAP) or triethylamine, described aprotic solvent is for example carrene, dimethyl formamide or dimethyl sulfoxide (DMSO), preferred 1-[3-(dimethylamino) propyl group]-3-ethyl carbodiimide and dimethyl aminopyridine be in dimethyl formamide. Above-mentioned reaction can be carried out under 22 ℃ to 60 ℃ temperature 1 hour to 20 hours, carried out 18 hours under preferred 22 ℃.
The compound of general formula V also can be by the compound of general formula X (for example, 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-and chlorobenzoyl chloride) prepare, comprise that the compound with itself and general formula X IV reacts in the presence of alkali, described alkali is in aprotic solvent, wherein said alkali includes but not limited to, dimethyl aminopyridine (DMAP), triethylamine, sodium hydrate aqueous solution or potassium hydroxide aqueous solution, and wherein said aprotic solvent for example is, carrene, ethyl acetate, dichloroethanes, dimethyl formamide or dimethyl sulfoxide (DMSO), preferred sodium hydrate aqueous solution and dichloroethanes. Above-mentioned reaction can be carried out under 22 ℃ to 60 ℃ temperature 1 hour to 24 hours, preferably carried out at ambient temperature 3 hours.
Compounds X can be prepared by Compound I X; be included under 22 ℃ to 60 ℃ the temperature; for example thionyl chloride or ethanedioly chloride are in for example reaction 1 to 24 hour in ethyl acetate, carrene or the dichloroethanes of polar non-solute with the reagent that can produce acid chloride with it, and preferably ethanedioly chloride reacted in carrene 16 hours at ambient temperature.
Scheme 3 relates to the preparation of the compound of general formula I X, can convert it into the compound of general formula V by scheme 2 described methods. The compound of general formula I X can be prepared with the decarboxylation condition by the compound of general formula X I, and preferred TGA is comprising for example reaction 1 hour to 24 hours under 22 ℃ to 160 ℃ temperature in the water of NaOH of alkali, preferably 100 ℃ of lower reactions 18 hours.
Scheme 4 relates to the preparation of the compound of general formula X III and XI. The compound of general formula X I can be changed into the compound of general formula I X by scheme 3 described methods.
The compound of general formula X I can be prepared by the compound of general formula X III, wherein R8(C1-C
2) alkyl, comprise itself and sour for example 50% sulfuric acid are reacted under 60 ℃ to 120 ℃ temperature, generally reacted 30 minutes to 6 hours, preferably 120 ℃ of lower reactions 2 hours.
The compound of general formula X III, wherein R8(C1-C
2) alkyl, diazonium intermediate that can origin self-drifting XII compound prepares. The preparation of this diazonium intermediate, comprise compound and for example hydrochloric acid and/or glacial acetic acid reaction of acid with general formula X II, then under 0 ℃ to 25 ℃ temperature, be used in solvent for example the natrium nitrosum in the water process, this reaction was generally carried out 30 minutes to about 2 hours, preferably reacted 30 minutes at 10 ℃. The compound of preparation general formula X II comprises the compound with above-mentioned diazonium intermediate and general formula X VII:
R
8O(C＝O)N(C＝O)CH
2(C＝O)N(C＝O)OR
8Under alkali condition, react. This reaction typically use sodium acetate as alkali at 0 ℃ to 120 ℃, carry out under the preferred 10 ℃ temperature, then be heated to 120 ℃, this reaction was generally carried out 1 hour to 24 hours, the preferred 4 hours (people such as Carrool; J.Med.Chem., 1983,26,96-100).
Those of ordinary skill in the art will appreciate that in some cases, base during preparation may need protection. After making target molecule; can remove protecting group with method known to a person of ordinary skill in the art; described method is for example at Greene and Wuts, described in " Protective Groups in Organic Synthesis " (3rd Ed, John Wiley ﹠ Sons 1999).
Comprise in the table 1 those with the example of such scheme and the explanation compound that can make:
Table 1
III. crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-preparation of benzamide
Can obtain its different crystal form by crystalline drug reactive compound from one or more organic solvents. The crystal form of the separation that obtains can comprise one or more organic solvents-" residual organic solvent ". In some cases, the amount of residual organic solvent need to be reduced to and regulate the acceptable level of medium (regulatory agency) (referring to for example Dwivedi (November 2002) Pharmaceutical Tech. 42-46 page or leaf in crystal form; With Guidance for Industry, Q3C Impurities:Residual organic solvents, U.S.Food and Drug Administration, Rockville, Maryland, December 1997), and the character relevant with preparing final unit dosage form (for example, stability, operation etc.) is compatible.
U.S. Patent Application Serial Number 10/748,340 embodiment 61 discloses a kind of 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystalline articles of benzamide, wherein measure by differential scanning calorimetry (DSC), it has 105.8 ℃ of single initial fusing points (heat absorption), carries out as 5 ℃/minute from 30 ℃ to 300 ℃ take the rate of heat addition. In some embodiments of the present invention, 2-chloro-N-of the present invention (1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystalline articles of benzamide, by determine with dsc method, its initial fusing point that has is between 108 ℃ ± 0.5 to 112 ℃ ± 0.5.
In some embodiments, preparation 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal form of benzamide, be included in and produce 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3 in the solution that comprises one or more organic solvents, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal of benzamide. Those skilled in the art can change various factors, comprise 2-chloro-N-in the solution (1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-concentration of benzamide, solvent composition, adding 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal seed of benzamide, the time in each step and temperature, solution in 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-purity of the initial substance of benzamide, the purity of employed solvent etc., obtain required crystalline solid.
In some embodiments, initial substance is 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide, it before by crystallization, then was dissolved in the solvent again. In addition, also can use various technology, for example then heating cools off 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-solution of benzamide, to obtain crystalline solid. In some embodiments, solution is cooled to 20 to 27 ℃, 10 to 22 ℃, 0 to 12 ℃, or-10 to 2 ℃ etc. In some embodiments, solution is heated to temperature between 40-60 ℃. Can be with 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide joins in the solution of one or more organic solvents, heating, then carry out following one or more steps, comprise: concentrated this solution, cool off this solution to (for example, 20 to 27 ℃ of lower temperatures, 10 to 22 ℃, 0 to 12 ℃ ,-10 to 2 ℃ etc.), and add crystal seed.
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystallization of benzamide can be in the result who carries out under environment temperature, higher temperature or the lower temperature and in the time of different length reaching required, this depends on various situations, for example the character of the character of technology and one or more organic solvents. Induced crystallization can comprise the following steps, comprise and change temperature (for example reducing temperature), add solvent and in crystallization solution, add a small amount of (or as seed) 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide.
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide can crystallization from the solution that comprises single organic solvent. By heating (for example, to 50 and 70 ℃ temperature), can be with 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide is dissolved in solvent (for example acetone, acetonitrile, N, N-dimethylacetylamide, N, dinethylformamide, dimethyl sulfoxide (DMSO), chloroform, ethyl acetate and methyl alcohol) in, then be cooled to lower temperature, until crystalline solid in solution, occurs.
In addition, 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide can obtain from the solvent system that comprises two or more relatively miscible solvents. In addition, 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide can crystallization from the first solution of one or more organic solvents, wherein in this solution solvent each other the phase commute mix and wherein this compound be suitably soluble, then with itself and one or more the second solvent, this second solvent is relative miscible with the first solution, 2-chloro-N-in the second solvent (1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-solubility of benzamide is than medium and small many of the first solution. Can suitably dissolve 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-example of the solvent of benzamide comprises acetone, acetonitrile, N, N-dimethylacetylamide, DMF, dimethyl sulfoxide (DMSO), carrene, chloroform, ethanol, ethyl acetate, methyl ethyl ketone, methyl alcohol and oxolane. In some embodiments, 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-solubility of benzamide in the second solvent is less than the about 20mg/ml of about 1-. In other embodiments, 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-solubility of benzamide in the second solvent is about 5 to about 20mg/ml. In other embodiments, 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide is suitably soluble in solvent, its solubility is about 50 to greater than 190mg/ml. 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3 in some embodiments, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide is suitably soluble in solvent, its solubility is about 20 to greater than 190mg/ml. In other embodiments, 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide is suitably soluble in solvent, its solubility is about 50 to about 180mg/ml. The example of the second suitable solvent comprises cyclohexane, normal heptane, phenmethylol, hexane, isopropyl alcohol, diisopropyl ether, methylisobutylketone, toluene, He Shui. The second solvent can be with slow, medium or add fast speed and mix with the first solution.
By being heated to a certain temperature (for example 55 ℃), can be 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide is dissolved in the solvent (for example acetone). Then cool off this and comprise 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-acetone soln of benzamide is to environment temperature, by adding 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal seed of benzamide comes induced crystallization, and then adds normal heptane.
Isolation of crystalline 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3 from solution, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide can use one or more technology, or their combination, for example filter, pass into air-flow, centrifugation, evaporation and the drying (for example under the environmental condition or in the vacuum desiccator of environment or higher temperature (for example 40-50 ℃)) of air or inert gas (for example nitrogen or argon gas) to sample. In some embodiments, the crystalline solid that so prepares comprises the residual organic solvent less than 2.5%. In some embodiments, by determine with dsc method, the initial fusing point that the crystalline solid for preparing like this has is between 108 ℃ ± 0.5 to 112 ℃ ± 0.5.
Crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxy-3-methoxy-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-feature of benzamide describes
Can use one or more technology that crystalline solid is carried out feature and describe, comprise polarization microscope detection, differential scanning calorimetry, thermogravimetry and/or X-ray powder diffraction (" XPRD ") method. For example, differential scanning calorimetry can be used for determining that sample shifts with respect to the heat of temperature, comprises the initial fusing point of sample.
Measure in order to carry out the X-ray powder diffraction at XPRD instrument (for example Shimadzu or Bruker instrument), typically sample is placed on the fixator with a cavity. With slide or analog push down sample powder with guarantee to have at random the surface and suitable height of specimen. Then sample fixer is placed instrument. X-beam radioactive source is positioned on the sample, and there is a less angle on the plane with respect to fixator during beginning, and moves along the arc that increases continuously angle between the plane of incident beam and fixator. The mensuration difference relevant with the analysis of described X-ray powder derives from many factors, comprise: (a) error in the sample preparation (for example, height of specimen), (b) instrument error (for example, flat sample error), (c) calibration error, (d) operator error (being included in the error that exists when determining the peak position), and (e) preferred orientation. Calibration error and height of specimen error can cause all peaks to identical direction with identical amount drift. The less difference of height of specimen can cause the larger displacement of XRPD peak position on level and smooth fixator. Systematic Study shows, if use Shimadzu XRD-6000 in typical Bragg-Brentano configuration, the height of specimen difference of 1mm can cause 1 ° of 2 θ of peak shift, and (Chen waits the people, J.Pharmaceutical and Biomedical Analysis, 2001; 26:63). These drifts can identify from x-ray diffraction pattern, can by this drift of compensation (give all peak position values systemic correction factor is provided) or again calibration instrument proofread and correct.
Powder X-ray diffraction figure also can be upper the analysis out of Inel (capillary) diffractometer (for example, Inel XRG-3000 diffractometer is equipped with sensitive (CPS) detectors of curve location of 2 θ scopes of 120 degree). Use CuKαRadiation begins to proofread and correct real time data with the resolution ratio of 0.03 ° of 2 θ from about 4 ° of 2 θ. The settings of tube voltage and amperage can be respectively for example 40kV and 30mA. Typically, sample is packed in the thin-walled glass capillary, prepare to be used for analyzing. General each capillary installs on the goniometer head, this goniometer head be motorization in order to allow to carry out rotation capillaceous in data acquisition period. Finish the instrument calibration of every day with the silicon reference standard. Come calculating strength from these figure, the technical scope that this belongs to this area comprises with deducting baseline and comes compensate for background scattering (for example by scattering capillaceous).
As mentioned above, possibly, the mensuration of the various XPRD instruments by the calibration of systemic calibration factor can be calibrated the mensuration of various machines the peak position is brought into consistent zone. Usually, a calibration factor will be brought the peak position into zone consistent with each other, and its scope is 0 to 0.2 ° of 2 θ.
In addition, crystalline solid can be used13The C-solid state NMR techniques is analyzed, with13Determine one or more peaks of PPM in the C-solid state spectrum. For example, crystalline solid can be filled into 4mm ZrO in spigot, under environmental pressure, on the Bruker 4mm BL CPMAS probe in being placed into wide-bore Bruker-Biospin Avance DSX 500MHz NMR spectrometer, uses1H-
13C cross polarization magic angle spinning technology (CPMAS) is collected one dimension at 293K13The C spectrum. Then sample spins with 15.0kHz, and cross polarization time of contact is 2.3ms, and the decoupling zero power setting is 85kHz. Typically the carbon spectrum, arranges its highfield resonance and is specific ppm value, for example 29.5ppm as reference with the outer sample of adamantane.
Can use various technology to determine the percentage of residual organic solvent (w/w), for example gas chromatography (" GC ") head space gas analysis (referring to for example, B ' Hymer (2003) Pharm.Res. 20:337-344). In the gas analysis of GC head space, typically collect the sample gas of sample top, with gas chromatography system that detection system (for example flame ionisation detector (FID) or mass spectrograph (MS)) links to each other in analyze. In addition, can make the headspace solid-phase microextraction (SPME) for example of ining all sorts of ways determine the level of residual organic solvent.
IV. the in-vitro evaluation of compound
Can determine the activity of compound of the present invention according to one or more following mensuration to above-mentioned various diseases.In following external test, the IC of all compounds of the present invention after measured
50Less than 10 μ M.
Preferably in following external test, the IC of The compounds of this invention
50Less than 100nM, be more preferably less than 50nM, most preferably less than 10nM.In addition, the preferred IC of compound of the present invention
50Scope is 0.01nM-100nM, more preferably 0.05nM-50nM, and 0.10nM-10nM most preferably.
Pharmacology is analyzed
Known some compound for example benzoyl benzoyl Triphosaden (bbATP) is P2X
7The agonist of acceptor, its in plasma membrane, influence the hole formation (Drug DevelopmentResearch (1996),
37 (3), p.126).Therefore, when activating this receptor with bbATP in the presence of bromination second pyridine (a kind of dna probe of fluorescence), the fluorescence that observes in the cell with the pyridine of DNA-bonded bromination second increases.Perhaps, can substitute the pyridine of bromination second with propidium dyestuff YOPRO-1, to survey the absorption of this dyestuff.The increase of fluorescence can be used as P2X
7The standard of receptor activation, therefore can the quantification compound to P2X
7The effect of acceptor.
In the method, can test compound of the present invention to P2X
7The antagonistic activity of acceptor.Tried solution with 250 μ l and fill the flat titer plate in 91-hole, this is tried solution and comprises 200 μ l and contain 10
-4The suspension (2.5 * 10 of the THP-1 cell of M bromination second pyridine
6Individual cell/ml more preferably stimulates to promote expression of receptor with LPS and TNF in advance according to document is described), 25 μ l contain 10
-5The hyperkalemia hyponatremia damping fluid of M bbATP (5mM D-glucose and 1.0%FBS, pH 7.5 for 10mM Hepes, 150mM KCl) and 25 μ l contain 3 * 10
-5M test-compound (more preferably 5 * 10
-4M, more preferably 1 * 10
-4M, more preferably 1 * 10
-3M) high potassium buffered soln.Cover this flat board with plastic plate, cultivated 1 hour at 37 ℃.Then should flat board reading in Perkin-Elmer fluorescence plate reader, 520nm excites, and the 595nm emission is stitched wide: Ex 15nm, Em 20nm.In order to compare fluorescence, can in test, use bbATP (P2X respectively
7Receptor stimulant) and 5-pyridoxal phosphate (P2X
7Receptor antagonist) in contrast.From the reading that obtains, can calculate the pIC of each test-compound
50Value, this value be reduce the essential test-compound of 50% bbATP agonist activity concentration over against number.
In similar method, also can measure compound of the present invention to P2X as readout with cytokine IL-1 β
7The antagonistic activity of acceptor.Use (Westchester, the normal subjects's that LSM PA) will be collected blood classification in the presence of heparin from Organon Technica.Collection comprises the zone of the monocytic resultant gradient of strip, keeps substratum (RPMI 1640,5%FBS, 25mM Hepes, pH 7.2,1% penicillin/streptomycin) dilution, centrifugation collecting cell with 10ml.Resulting cell precipitation is suspended in 10ml keeps in the substratum, carry out cell counting.In average experiment, each hole of 96-orifice plate has all inoculated 2 * 10
5Individual monocyte, cumulative volume are 0.1ml.Monocyte was adhered to 2 hours, get rid of supernatant liquor then, with attached cell flushing twice, then at 37 ℃ and 5%CO
2In keeping substratum, cultivate in the environment.
Can use 10ng/ml LPS (e. coli serotype 055:B5; Sigma Chemicals, St.Louis MO) activates the monocyte of cultivating.Cultivate after 2 hours, remove activating medium, (RPMI 1640,1%FBS, 20mM Hepes, 5mMNaHCO with 0.1ml Chase substratum
3, pH 6.9) and with cell flushing twice, add the 0.1mlChase substratum that comprises the agent of being had a try then, should cultivate 30 minutes by flat board; Can in triplicate any hole, calculate the concentration of each agent of being had a try.Induce ATP (from the 100mM mother liquor, pH 7) to reach the ultimate density of 2mM then, under 37 ℃, flat board was cultivated 3 hours again.Trapping medium, centrifugation make it to become clarification, with ELISA (R﹠amp; D system; Minneapolis MN) determines their IL-1 β content.
V. pharmacologically acceptable salts
Compound of the present invention (for example, the compound of general formula I) can further form pharmacologically acceptable salts, includes but not limited to sour addition and/or base addition salt.The pharmacologically acceptable salts of the compound of general formula (I) comprises its sour addition and base addition salt (comprising disalt).The example of suitable salt can be at for example Stahl and Wermuth, Handbook ofPharmaceutical Salts:Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002); With people such as Berge, " PharmaceuticalSalts, " J.of Pharmaceutical Science, 1977; Find among the 66:1-19.
The acceptable acid salt of the pharmacy of the compound of general formula I comprises the avirulent salt from mineral acid, for example hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, Hydrogen bromide, hydroiodic acid HI, phosphorus or the like, and from organic acid salt, for example aliphatics single-and dicarboxylic acid, phenyl paraffinic acid, hydroxyl alkane acid, chain docosandioic acid, aromatic acid, aliphatics and aromatic sulphonic acid of replacing or the like.These salt comprise the acetate of the compound of general formula I, aspartic acid, benzoate, benzene sulfonate (besylate), bicarbonate/carbonate, hydrosulfate, octylate, d-camphorsulfonic acid (camsilate), chloro-benzoic acid, Citrate trianion, ethanedisulphonate (1, the 2-ethane disulfonate), dihydrogen orthophosphate, dinitro-benzoate, esilate (ethane sulfonate), fumarate, gluceptate, gluconate, glucuronate, hibenzic acid salt, hydrochloride/muriate, hydrobromide/bromide, hydriodide/iodide, isobutyrate, monohydric phosphate, isethionate, D-lactate, the L-lactic acid salt, malate, maleate, malonate, mandelate, mesylate (methanesulfonate), metaphosphate, tolyl acid salt, Methylsulfate, 2-naphthyl sulfonate (2-naphthalenesulfonate), nicotinate, nitrate, Orotate, oxalate, palmitate, phenylacetate, phosphoric acid salt, phthalate, propionic salt, pyrophosphate salt, pyrosulphate, saccharate, sebacate, stearate, suberate, succinate, vitriol, sulphite, the D-tartrate, the L-tartrate, tosylate (toluene sulfonate), with xinafoate or the like.What pay close attention to simultaneously is for example arginic acid salt, gluconate, galacturonic hydrochlorate or the like of amino acid whose salt.
The preparation of the acid salt of basic cpd comprises according to ordinary method free alkali form is contacted to make salt with the required acid of q.s.This free alkali form of can regenerating comprises according to the form of ordinary method with salt contacting separated free alkali with alkali.For example aspect the solvability in polar solvent, how many free alkali forms is different from their salt forms separately in some physical properties, but for purpose of the present invention, this salt is identical with their free alkalis separately.
The acceptable base addition salt of pharmacy is with metal or amine, and for example the oxyhydroxide of basic metal and alkaline-earth metal or its organic amine form.Ion as cationic metal is aluminium, calcium, magnesium, potassium, sodium or the like.The example of suitable amine is arginine, choline, chloroprocaine, N, N '-Dibenzylethylenediamine, diethylamine, diethanolamine, diethanolamine, bitter edible plant alkali quadrol (ethane-1,2-diamines), glycine, Methionin, meglumine, N-methyl glucoside amine, thanomin, PROCAINE HCL, PHARMA GRADE (benzylic penicillin) and tromethane.
The base addition salt of preparation acidic cpd comprises that the method according to routine contacts free acid form to make salt with the required alkali of q.s.Regeneration free acid form comprises that the method according to routine contacts separated free acid with salt form with acid.For example aspect the solvability in polar solvent, how many free alkali forms is different from their salt forms separately in some physical properties, but for purpose of the present invention, this salt is identical with their free acids separately.
VI. pharmaceutical composition and medication
The present invention also provides pharmaceutical composition, crystal 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 of containing that comprises the treatment significant quantity less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide mixes with at least a pharmaceutically acceptable carrier, pharmaceutical composition comprises: the 2-chloro-N-that contains residual organic solvent (1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 of treatment significant quantity, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide mixes with at least a pharmaceutically acceptable carrier, wherein pass through determine with dsc method, described 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-initial fusing point that benzamide has is between 108 ℃ ± 0.5 to 112 ℃ ± 0.5.Preparation 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-pharmaceutical composition of benzamide, comprise at least a pharmaceutically acceptable carrier and crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-the benzamide mixing.
Term " pharmaceutical composition " relates to and is adapted at the composition used in medical science or the veterinary science.Term " treatment significant quantity " is meant when using separately or with other pharmaceutical agent treats particular patient or patient's group time, and the amount of compound or its pharmacologically acceptable salts is enough to suppress, stop, or improves the disease that will treat.For example in people or other Mammals, when being used for the treatment of specified disease or patient, the treatment significant quantity can be in laboratory or clinical setting determines according to experiment, or according to the aequum that U.S. food and drug administration instruct, perhaps equates with the standard of foreign mechanism.
Should be appreciated that suitable formulation, dosage and route of administration fix within the level of pharmacy and medical field those of ordinary skill really, and as described below.
Compound of the present invention can be mixed with the pharmaceutical composition of forms such as syrup, elixir, suspension, powder, particle, tablet, capsule, lozenge, lozenge, the aqueous solution, emulsifiable paste, ointment, lotion, gel, emulsion, preferably, by quantitative or qualitative test, compound of the present invention will cause symptom relevant with the illness of IL-mediation or disease performance to reduce.
When from compound pharmaceutical composition of the present invention, pharmaceutically acceptable carrier can be solid or liquid.But the preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and discrete particles.Liquid vehicle can be one or more materials that can be used as thinner, seasonings, tackiness agent, sanitas, tablet disintegrant or coating material.
In powder, carrier is pulverizing solid, during itself and pulverizing active ingredient mix.In tablet, active ingredient is mixed with the carrier with necessary bond property of suitable proportion, is pressed into required shape and size.
Powder and tablet comprise the active compound of 1% to 95% (w/w).In some embodiments, the scope of this active compound is 5% to 70% (w/w).Appropriate carriers is magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil or the like.Term " preparation " is the preparation that comes the coating active compound with carrier, wherein said preparation be with coating material as carrier provide a kind of contain active ingredient and/do not contain the capsule of other carriers, therefore carrier and active compound are combined.Similarly, in cachet and lozenge are also included within.Tablet, powder, capsule, pill, cachet and lozenge can be as being fit to oral solid dosage.
When preparation suppository, at first dissolve low melt wax, for example the mixture of glycerin fatty acid ester or theobroma oil is scattered in active ingredient wherein equably by stirring then.Then the uniform mixture of fusing is poured in the conventional capacity mould, cooling is solidified then.
Liquid absorption member comprises solution, suspension and emulsion, for example, and water or water/propylene glycol solution.When parenteral was injected, liquid preparation can be mixed with solution in the aqueous solution of polyoxyethylene glycol.
Be fit to the preparation of the oral aqueous solution, comprise solubilization of active ingredient in water, adding appropriate colouring agent, flavouring agent, stablizer and thickening material if desired.Be fit to the preparation of oral aqueous suspension, comprise pulverizing active ingredient and viscous substance are distributed in the water that described viscous substance is for example natural or synthetic glue, resin, methylcellulose gum, Xylo-Mucine and other known suspending agents.
Be also included within the preparation that is transformed into the solid form of oral liquid before the use immediately.These liquid forms comprise solution, suspension and emulsion.Except active ingredient, these preparations comprise tinting material, flavouring agent, stablizer, buffer reagent, artificial and natural sweetener, dispersion agent, thickening material, stablizer or the like.
Pharmaceutical preparation is unit dosage preferably.In this formulation, preparation is subdivided into the unitary dose that comprises the appropriate amount active ingredient.This unit dosage can be the preparation of packing, and this packing comprises discrete preparation, for example the tablet of packing in vial or ampoule, capsule and powder.Equally, unitary dose can be its capsule, tablet, cachet or lozenge, and perhaps it can be any above-mentioned formulation of proper amt in these packaged forms.
According to the specific application and the usefulness of active ingredient, the amount of active ingredient can be various in unit dose formulations, perhaps can be from 0.1mg to 1000mg, and preferred 1.0mg is to 100mg, or unitary dose 1% to 95% (w/w).If desired, said composition also can comprise other compatible therapeutical agents.
Pharmaceutically acceptable carrier can be determined by the particular composition that will use and by the ad hoc approach of administered compound to a certain extent.Therefore, just exist kind widely the suitable preparation of pharmaceutical composition of the present invention (referring to, Remington:The Scienceand Practice of Pharmacy for example, 20th ed., people Eds. such as Gennaro, Lippincott Williams and Wilkins, 2000).
Compound of the present invention, separately or with other suitable combination of components, can make aerosol formulation (that is, they can " be sprayed ") and use through suction.Aerosol formulation can be inserted in the acceptable propellent of pressurization, for example Refrigerant 12, propane nitrogen or the like.
Suitable parenteral is the preparation used of vein, intramuscular, intradermal and subcutaneous route for example, comprise water-based and nonaqueous isotonic sterile injection solution, it can comprise antioxidant, buffer reagent, fungistat and make preparation and expection recipient's the isoosmotic solute of blood; With water-based and nonaqueous sterile suspension, it can comprise suspending agent, solubilizing agent, thickening material, stablizer and sanitas.Implementing when of the present invention, said composition can be by using in venoclysis, oral, local, intraperitoneal, intravesical or the sheath.The sealed vessel that the preparation of compound may reside in unitary dose or multiple doses is for example in ampoule or the vial.Injection solution or suspension also can be prepared by sterilized powder, particle and the tablet of mentioned kind.
In the context of the present invention, the dosage of using to the patient should be enough to produce over time useful therapeutic response in the patient.Term " patient " relates to a mammiferous member.Mammiferous example includes but not limited to, people, primates, orangutan, rodent, mouse, rat, rabbit, horse, domestic animal, dog, cat, sheep and ox.
The body surface area that effectiveness that can be by employed specific compound, patient's situation and body weight or patient will treat is determined dosage.Existence, the nature and extent of any adverse side effect that the size of dosage also can occur together when using specific compound in particular patient are determined.When the significant quantity of the compound of determining to be applied to the treatment of conditions that will treat or prevention, the doctor can estimate various factors for example circulating plasma level, the toxicity of compound and/or the progress of disease or the like of compound.Usually, for typical patient, the dose equivalent(DE) of compound is that about 1 μ g/kg is to 100mg/kg.Many different medications all are known for those skilled in the art.
When using, compound of the present invention can be used with the speed of being determined by following factor, these factors can include but not limited to, the pharmacokinetic curve of compound, incompatible medicine, the side effect of compound when different concns are to be fit to patient's weight and holistic health.Can finish by list or broken dose and use.
The example of typical tablet, parenteral and patch preparation can comprise as follows:
Tablet formulation embodiment 1
Tablet formulation
Become component
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl 50mg
-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro
-3H-[1,2,4] triazine-2-yl]-benzamide, comprise 0.17% residual organic solvent
Lactose 80mg
Corn starch (being used for mixing) 10mg
Corn starch (being used for bonding) 8mg
Magnesium Stearate (1%) 2mg
150mg
Compound of the present invention (for example compound of general formula I, or its pharmacologically acceptable salts) can be mixed into uniform powder with lactose and corn starch (being used to mix).Corn starch (being used for bonding) is suspended in 6mL water, and heated and stirred forms paste.This paste is joined in the powder that mixes this mixture of granulation.This wet granular is sieved firmly by No. 8,50 ℃ of dryings.With lubricated this mixture of 1% Magnesium Stearate, be pressed into tablet.With every day 1 to 4 frequency this tablet is applied to the patient, be used for the treatment of the disease (for example, rheumatoid arthritis) of IL-1 mediation.
Parenteral admin pharmaceutical solutions embodiment 1
In the solution of 700mL propylene glycol and 200mL water for injection, adding 20.0g comprises 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 of 0.17% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide.Stir this mixture, regulate pH to 5.5 with hydrochloric acid.With the water for injection adjusted volume to 1000mL.With this solution sterilization, be encased in the 5.0mL ampoule, comprise 2.0mL (40mg compound of the present invention) in every ampoule, at the nitrogen lower seal.By injection this solution is applied to the disease (for example, rheumatoid arthritis) of suffering from the IL-1 mediation and the patient who needs treatment.
Patch preparation embodiment 1
10mg is comprised 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 less than 0.17% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide and 1mL propylene glycol and the 2mg that contains resin cross-linking agent mix based on polymerizing acrylic acid thing tackiness agent.This mixture is applied to (30cm in the impermeable back of the body
2) and be applied to patient's last back, be used for the lasting release treatment of the disease (for example, rheumatoid arthritis) of IL-1 mediation.
VII. treat the method for the disease of IL-1 mediation
Compound of the present invention, composition and pharmaceutical composition can be applied to the patient of the disease of suffering from the IL-1 mediation.
With compound of the present invention can be prophylactically, acute treatment ground or treat the disease of IL-1 mediation chronically, this depends on the character of disease.Typically in each of these methods, host or patient are the people, although other Mammalss also can be benefited from the using of compound of the present invention.
When therapeutic was used, compound of the present invention can be prepared into the oral widely and parenteral dosage form of kind, and uses.Term administering " relate to the method that compound is contacted with the patient.Therefore, compound of the present invention can be used by injection, that is, and and in intravenously, intramuscular, intracutaneous, subcutaneous, the duodenum, parenteral or peritoneal injection.Simultaneously, described chemical combination property can be used by suction, for example sucks in the nose.Compound of the present invention in addition can be through skin, part, by implanting, using through skin, part with by implantation.In some embodiments, compound of the present invention passes through oral delivery.This compound also can per rectum, cheek, intravaginal, eye, andially, or sends by being blown into.
The compound that utilizes in method of pharmacy of the present invention can be used to about 100mg/kg with predose about 0.001mg/kg every day.In some embodiments, every day, dosage range was that about 0.1mg/kg is to about 10mg/kg.But, this dosage can according to patient's needs, to treat situation severity with the compound of being used and different.Determine that suitable dosage under the particular case is in practitioner's technical capacity.Usually, general with low dose of begin treatment less than the compound optimal dose.Then, increase dosage with less amplitude, until reaching best effect in all cases.For convenience, can cut apart total dosage every day, if desired, gradation is used in one day.Term " treatment " comprises fast, alleviates or alleviate for a long time or prophylactically relevant with the treatment illness or by its at least a symptom or feature that causes.For example, treatment can comprise several symptoms that alleviate illness, suppresses the pathology development of illness, or eradicates illness fully.Compound of the present invention can Combined Preparation in the patient.Term " Combined Preparation " is meant the combination by identical pharmaceutical composition or isolating pharmaceutical composition, uses two or more different pharmaceutically active agents or therapeutic modalities (for example, radiation therapy) to the patient.Therefore, Combined Preparation comprises uses the single pharmaceutical composition that comprises two or more pharmaceutically active agents at one time, perhaps uses two or more different compositions for same patient in the identical or different time.For example, the patient in the morning 8 used first dosage that comprises The compounds of this invention, behind on the same day 1 to 12 hour, for example select evening 6 and used second therapeutical agent then, be exactly in this patient so with compound of the present invention and the second therapeutical agent Combined Preparation.Perhaps, for example the patient 8 selects and uses the single dose that comprises the compound of the present invention and second therapeutical agent in the morning, and this also is with the compound of the present invention and the second therapeutical agent Combined Preparation.
Therefore, compound of the present invention can with other compound Combined Preparation, wherein these compounds can be used for the treatment of cancer (for example, cytotoxin class medicine TAXOL_, taxotere, GLEEVEC_ (imatinib mesylate), Zorubicin, daunorubicin, cis-platinum, Etoposide, vinca alkaloids, vinealeucoblastine(VLB), vincristine(VCR), methotrexate or Zorubicin, daunorubicin, Etoposide and alkaloid vincristine(VCR), farnesyl transferase, endostatin and angiostatin, VEGF inhibitor and metabolic antagonist methotrexate for example for example for example.Compound of the present invention also can be used for and Taxane derivative, platinum coordination complex, nucleoside analog, anthracycline antibiotics, topoisomerase enzyme inhibitor or aromatase inhibitor combination).Radiation therapy also can be treated cancer with compound Combined Preparation of the present invention.
Compound of the present invention can with other compound Combined Preparation, wherein these compounds (for example can be used for the treatment of thrombus disease, heart disease, apoplexy or the like, acetylsalicylic acid, streptokinase, tissue plasminogen activator, anti-coagulant, antiplatelet drug (for example, PLAVIX_; SR-25990C), statins (for example, LIPITOR_ (atorvastatin calcium), ZOCOR_ (Simvastatin), CRESTOR_ (superstatin) etc.), beta-Blocking agent (for example, atenolol USP 23), NORVASC_ (Amlodipine Besylate) and ACE inhibitor (for example, Accupril_ (quinapril hydrochloride), lisinopril etc.).
Compound of the present invention also can with compound for example ACE inhibitor, lipid lowering agent for example statins, LIPITOR_ (atorvastatin calcium), calcium channel blocker for example NORVASC_ (Amlodipine Besylate) Combined Preparation be used for the treatment of hypertension.Compound of the present invention also can be used for and fibrosing agent, beta-Blocking agent, NEPI inhibitor, Angiotensin-2 receptor antagonist and anticoagulant combination.
When the treatment inflammatory diseases, when comprising rheumatoid arthritis, the present invention can with following reagent Combined Preparation: TNF-alpha inhibitor anti-TNF alpha monoclonal antibody (for example REMICADE_, CDP-870 and HUMIRA for example for example
TM(adalimumab) and TNF receptor-immunoglobulin fusion molecule (for example ENBREL_), RITUXAN_ (Rituximab), IL-1 inhibitor, receptor antagonist or soluble IL-1R α (KINERET for example
TMOr ICE inhibitor), the IL-6 monoclonal antibody, the IL-6 acceptor monoclonal antibody (for example, MRA (Chugai)), the M-CSF monoclonal antibody, NSAID (non-steroidal anti-inflammatory drug) (NSAIDS), piroxicam, diclofenac, Naproxen Base, flurbiprofen, fenoprofen, Ketoprofen, Ibuprofen BP/EP, fragrant that ester class, mefenamic acid, indomethacin, sulindac, Azapropazone, pyrazolone, Phenylbutazone, acetylsalicylic acid, cox 2 inhibitor (for example, CELEBREX_ (celecoxib), VIOXX_ (rofecoxib), BEXTRA_ (valdecoxib) and L-791456), inhibitors of metalloproteinase (preferred MMP-13 selective depressant), NEUROTIN_, Pregabalin, the low dosage methotrexate, sulfasalazine, obey Mi Te, Plaquenil, the d-Trolovol, auranofin or parenteral or oral contain golden thing.
Compound of the present invention can be treated osteoarthritis with already present therapeutical agent Combined Preparation.The suitable reagent that uses in this combination comprises standard NSAID (non-steroidal anti-inflammatory drug) (making NSAID ' s down) for example piroxicam, diclofenac; Propionic acid is Naproxen Base, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP for example; Fragrant that ester class is mefenamic acid, indomethacin, sulindac, Azapropazone for example; Pyrazolone is Phenylbutazone for example; Salicylic acid is acetylsalicylic acid for example; Cox 2 inhibitor is (celecoxib), rofecoxib, valdecoxib and L-791456 for example; Anodyne and intraarticular therapeutical agent be reflunomide for example; For example Hyalgan and Xin Wei can (synvisc) with glass acid.
Compound of the present invention also can with antiviral agent viracept see nelfinaivr, AZT, acyclovir and Famciclovir and preservative compound Valant Combined Preparation for example for example.
In addition, compound of the present invention can with following reagent Combined Preparation: the CNS agent is thymoleptic (for example Sertraline) for example, antiparkinsonism drug (selegiline for example, levodopa, Requip, Mirapex, the MAOB inhibitor is selegine and rasagiline for example, the comP inhibitor is tolcapone for example, the A-2 inhibitor, dopamine reuptake inhibitor, nmda antagonist, the Nicotine agonist, dopamine agonist and neural nitric oxide synthase inhibitors), NEURONTIN_, Pregabalin, with health alzheimer's disease medicine ARICEPT_ for example, tacrine, propentofylline or Metrifonate.
Compound of the present invention in addition can with following reagent Combined Preparation: the osteoporosis agent is for example FK-506 and rapamycin of EVISTA_ (RALOXIFENE HCL), droloxifene, Lasofoxifene or FOSAMAX_ and immunosuppressor for example.
Embodiment
Be to be understood that, embodiment as herein described and embodiment are only used for purpose of explanation, this will inspire those skilled in the art to carry out various changes or variation according to it, and these changes or change all in the application's spirit and scope, and in the scope of appended claim.For all purposes, whole publications, patent and the patent application of quoting in this article is all by being incorporated herein with reference to the integral body with them.
Intermediate 1.2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-N-(1-hydroxyl-suberyl methyl)-benzamide
Adding 7.50kg 2-chloro-5-in the glass-lined reactor of 200L (3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-phenylformic acid and 72L methylene dichloride, stir down at 20-22 ℃ then.In this suspension, add the 3.75L oxalyl chloride, last 5 minutes, add 75ml N then, dinethylformamide (DMF).The chloride of acid of resulting separation (2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-Benzoyl chloride on strainer then), with the isopropyl ether washing, dry up with nitrogen.When chloride of acid was dry on strainer, with 4.03kg 1-amino methyl-suberyl alcohol HCl, 2.31kg sodium hydroxide and 52.5L water joined in the 200L reactor, stirred until forming uniform solution.Then chloride of acid is joined in this solution, stirred 4 hours at 20-22 ℃, the reaction of HPLC analysis revealed is finished in this time.With 6N HCl reaction mixture is adjusted to pH 3 then, on strainer, separates thick intermediate 1 (2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-N-(1-hydroxyl-suberyl methyl)-benzamide then).Wash reactor and strainer with water, dry up thick intermediate 1.This intermediate 1 of recrystallization then, comprise with in this substance dissolves on the strainer in 75L methyl alcohol, be heated to 70 ℃, add 37.5L water, be cooled to 20 ℃.Stir after 12 hours, separation of intermediates 1 on strainer, water: methyl alcohol (2: 1) solution washing, drying is 48 hours in vacuum drier.Separate and obtain 8.0kg intermediate 1 (73% yield).Use d
6-DMSO carries out on Varian 400MHz spectrograph as solvent
1H NMR spectroscopic analysis.
1H NMR δ12.37(s，1H)，8.32-8.34(t，1H)，7.65(s，1H)，7.53-7.59(m，3H)4.24(s，1H)，3.32(s，1H)，2.49-3.20(d，1H)，2.48(m，2H)，1.33-1.63(m，10H).MS：393.1(M+1)。
Embodiment 1.2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide.
Add DMF 9.6L and silica gel 4.12kg in the glass-lined reactor of 200L, stir half an hour, the mixture that obtains is the slurry shape.Add intermediate 1 (2.75kg, 7 moles) then, mixture has become solution after stirring half an hour.Drip R-(-)-glycidyl methyl ether (954g, 10.5 moles) then, simultaneously the temperature of reactor is heated to 80 ℃ 16 hours.After HPLC analysis revealed reaction is finished,, add ethyl acetate 82.5L and precipitate silica gel reactor cooling to 25 ℃.Elimination silica gel is used 14L saturated sodium bicarbonate solution continuous extraction ethyl acetate layer 3 times then, then with the extraction of 14L water once.Under atmospheric pressure at the extremely about 14L of 76-78 ℃ of concentrated ethyl acetate layer, use 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 then, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide begins crystallization as crystal seed.On strainer, separate 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide, dry in vacuum drier during weekend, obtain the 2.5kg product, 74% yield.
1H ﹠amp;
13CNMR spectrum, the mass spectrum of 481.4 (M+1), and HPLC-UV all with 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-structure of benzamide meets.
Embodiment 2. mixes intermediate 1 (1g in test tube, 2.5mmol), DMF (3ml, 3vol), (R)-(-)-glycidyl methyl ether (230mg, 2.6mmol, 1.05 equivalents) and boron trifluoride diethyl ether compound (3.6mg, 0.025mmol, 0.1mol%), under nitrogen, be heated to 80 ℃ 16 hours.The HPLC-UV that carries out on ZORBAX_SB-CN post (0.2% phosphoric acid water: in the acetonitrile (1: 1)) analyzes and roughly shows, intermediate 1 and product 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-ratio of benzamide approximately is 9: 1.
Embodiment 3. adds 4.3kg synthetic 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 in embodiment 1 in the glass-lined reactor of 200L, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide, add ethyl acetate (130L) then.Reactor is heated to 78 ℃ then, makes 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide enters in the solution.Cooling reactor to 25 ℃ also water (21.5L) extraction then.Then ethyl acetate layer is transferred in 55 gallons the cylinder.Ethyl acetate layer shifts back in the 200L reactor by the filter in pipeline, under atmospheric pressure is concentrated into about 20L.
Get its part, place round-bottomed flask then, by beginning crystallization with the metallic rod friction.Filtering mixt, vacuum-drying obtain the crystal seed material.The crystal seed material is added back in the reactor, after the stirred for several hour, observes the heavy-gravity slurry at 0 ℃.Disposable adding normal hexane (8.6L) in the vacuum downhill reaction device stirs under-10 ℃ and spends the night then.On strainer, separate this material, then dry in vacuum drying oven during weekend.The GC-headspace analysis shows that this material comprises 2.6% residual ethyl acetate.Determine that with dsc (seeing below) the initial fusing point of this material is 106.5 ℃.
Determined the GC-headspace in these embodiments, comprised and use Agilent GC 6850Model G2630A, Hewlett Packard head space automatic sampler 7694 and DB642, DB-624,30m * 0.32mm I.D. fused silica, 1.8 μ m thin film columns.The program oven temperature that institute's using method has is: 40 ° (5 minutes), be heated to 46 ℃ with 2 ℃/minute then, be heated to 225 ℃ with 25 ℃/minute then, and kept 2 minutes at 225 ℃.Syringe is at 180 ℃.The post air-flow is the nitrogen of the about 8.5psi of flow velocity or 1.6ml/ minute.Shunting is about 47ml/ minute.Splitting ratio is about 30: l.The fid detector of use under 250 ℃.
Embodiment 4. adds 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 in the glass-lined reactor of 50L, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide (3.9kg) (from embodiment 3) and acetone (11.7L).Reactor is heated to 55 ℃ then, makes 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide enters solution.Then in 4 hours time with reactor cooling to 20 ℃, by in reactor, adding 2g crystal seed 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide comes induced crystallization.After 20 ℃ of stirrings are spent the night, observe the heavy-gravity slurry.Filtered sample, vacuum-drying then.The GC-headspace analysis shows 0.21% residual acetone (embodiment 4, sample A).
In pressure tank, add normal heptane (24L) by the filter in pipeline then, in 4 hours time, join the 50L reactor.Allow crystalline mixture spend the night at 20 ℃.Filtered sample is vacuum-drying then.The GC-headspace analysis shows 0.18% residual acetone (embodiment 4, sample B).On strainer, separate this material, dry up with nitrogen then and spend the night, then during weekend in vacuum drying oven (40-50 ℃) drying.The GC-headspace analysis shows 0.17% residual acetone (embodiment 4, sample C).
With dry more about 5.5 hours of this material (40-50 ℃) in vacuum drying oven, obtain embodiment 4, sample D then.
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-dsc of benzamide
On Mettler-Toledo 822e differential scanning calorimeter to embodiment 4, sample A; Embodiment 4, sample B; Embodiment 4, sample C; With embodiment 4, sample D carries out dsc (DSC).This method is used 1-5mg sample aluminium 40 μ l dish, and the beginning temperature is 30 ℃, and outlet temperature is 300 ℃.Heating rate is 5 ℃/minute.Sampling interval is 1 second.Nitrogen flow rate is 60ml/ minute.Embodiment 4, and the DSC calorifics collection of illustrative plates of sample D as shown in Figure 1.Detect the temperature that begins to melt at about 110.5 ℃.Embodiment 4, sample A; Embodiment 4, sample B; With embodiment 4, the beginning temperature of fusion of sample C is reported in table 2.
Table 2
| Sample | DSC mp |
| Embodiment 4, sample A | 111.3℃ |
| Embodiment 4, sample B | 111.4℃ |
| Embodiment 4, sample C | 111.3℃ |
| Embodiment 4, sample D | 110.5℃ |
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide, embodiment 4, and sample D's is solid-state
13C-NMR
Will about 70mg embodiment 4, the sample D 4mm ZrO that closely packs into is used for sample analysis in spigot.Under environmental stress, on the Bruker 4mm BL CPMAS probe in being placed into wide-bore Bruker-BiospinAvance DSX 500MHz NMR spectrometer, use
1H-
13C cross polarization magic angle spinning technology (CPMAS) is collected unidimensional at 293K
13The C spectrum.Sample spins with 15.0kHz, and this specifies roll rate consistent with 4mm from the maximum of spigot.Roll rate makes the intensity of spin sideband minimize fast.In order to optimize signal sensitivity, duration of contact is adjusted to 2.3ms in cross polarization, be 85kHz with the decoupling zero power setting.Obtain the carbon spectrum with 5,940 scannings with recirculation in 10 seconds delay., its upfield resonance is set is 29.5ppm as reference with diamantane external standard sample.
Resulting embodiment 4, sample D material
13C CPMAS spectrum as shown in Figure 2.Carbon peak table provides in table 3.Please note, the quantity at carbon peak and 2-chloro-N-(1-hydroxyl-suberyl methyl) in the table 3-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-carbonatoms in the benzamide molecule (structure 1) do not conform to.Some carbon in this molecule have shown 2
13The C peak, this matches with the not isomorphism type of observed each asymmetric cell in monoclinic crystal structure.
Structure 1
Table 3
| The peak | 13C displacement (ppm) | Intensity (arbitrary unit) | The peak | 13C displacement (ppm) | Intensity (arbitrary unit) |
| 1 | 169.8 | 6.22 | 18 | 66.9 | 2.42 |
| 2 | 156.8 | 9.11 | 19 | 65.1 | 3.55 |
| 3 | 149.3 | 2.83 | 20 | 60.4 | 5.82 |
| 4 | 148.4 | 2.77 | 21 | 57.2 | 5.19 |
| 5 | 140.6 | 4.38 | 22 | 53.4 | 3.14 |
| 6 | 139.7 | 4.56 | 23 | 50.4 | 0.13 |
| 7 | 138.7 | 9.47 | 24 | 43.9 | 1.85 |
| 8 | 136.9 | 3.13 | 25 | 40.0 | 1.76 |
| 9 | 132.2 | 4.5 | 26 | 38.2 | 6.84 |
| 10 | 131.9 | 4.49 | 27 | 37.3 | 5.47 |
| 11 | 130.8 | 5.5 | 28 | 36.6 | 2.7 |
| 12 | 129.5 | 3.7 | 29 | 31.4 | 3.11 |
| 13 | 128.7 | 3.55 | 30 | 29.3 | 5.2 |
| 14 | 126.5 | 2.71 | 31 | 23.2 | 4.48 |
| 15 | 125.2 | 2.6 | 32 | 22.7 | 3.96 |
| 16 | 74.0 | 12 | 33 | 20.4 | 3.04 |
| 17 | 73.1 | 3.68 | 34 | 19.2 | 1.06 |
2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-powder x-ray diffraction (PXRD) of benzamide (embodiment 4, sample D) analyzes
Collect x-ray diffraction pattern with Bruker D5000 diffractometer, described diffractometer is furnished with CuK α, and ((generator: 40kV 30mA), fixes seam (radiating slot: 1mm to (little focus X-ray-x ray tube) source of radiation; Scatter slit: 1mm; Accept seam: 0.6mm) and Kevex PSI or Sol-X solid-state detector.With the interval of 0.04 degree and pitch time of 1.0 seconds collecting data spending to 2 θ of 40.0 degree from 3.0.Scan mode is a continuity.2-θ value record is in table 4.
Table 4
Peak table (2-θ ± 0.2)
(according to granularity and form, peak intensity can change)
| 2-θ angle ° | Intensity % | 2-θ angle ° | Intensity % |
| 7.8 | 11 | 23.3 | 13.1 |
| 8.1 | 100 | 23.9 | 9.8 |
| 10.5 | 10.3 | 24.3 | 14.5 |
| 11.7 | 21.3 | 24.6 | 7.6 |
| 13.2 | 5.2 | 25.1 | 9.9 |
| 13.7 | 8.1 | 25.9 | 9.2 |
| 14.3 | 5.7 | 26.2 | 12.7 |
| 14.9 | 21.6 | 27.1 | 30.9 |
| 15.6 | 5.2 | 27.6 | 9.6 |
| 16.4 | 86.9 | 28.2 | 5.2 |
| 17.3 | 17.5 | 28.7 | 4.9 |
| 17.7 | 17.3 | 28.8 | 4.9 |
| 18.3 | 19 | 29.4 | 6.4 |
| 18.9 | 9.2 | 30.0 | 10.2 |
| 19.1 | 9.9 | 30.3 | 14 |
| 19.7 | 85.9 | 30.9 | 7.9 |
| 20.3 | 9.5 | 31.1 | 7.7 |
| 20.9 | 8.8 | 31.9 | 6.2 |
| 21.2 | 33.3 | 33.4 | 5.9 |
| 21.6 | 24 | 33.8 | 6.4 |
| 22.2 | 33.8 | 34.3 | 7.5 |
| 22.6 | 17.6 | 35.2 | 8.9 |
| 22.8 | 6.7 | 37.1 | 6.2 |
Embodiment 4, sample A; Embodiment 4, sample B; With embodiment 4, the x-ray diffraction pattern of sample C and embodiment 4, the diffractogram unanimity of sample D.
Embodiment 5-13
The initial substance of embodiment 5-13 is from embodiment 3.The x-ray diffraction pattern of embodiment 5-13 and embodiment 4, the diffractogram unanimity of sample D.
Embodiment 5
At 125 ℃ with 5g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide joins in the 50ml n-butyl acetate, be concentrated to 25ml then, filter resulting solid matter and drying in vacuum drier.
Embodiment 6
At 70 ℃ with 5g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide joins 25ml methyl ethyl ketone (MEK).Add the 25ml normal hexane, leach resultant solid matter and dry in vacuum drier.
Embodiment 7
With 19g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide sieves by hand, and dry in vacuum drier.
Embodiment 8
At 50 ℃ with 15.5g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide joins in the 75ml methyl alcohol.Cool off this solution then to envrionment temperature, add 75ml water and form oil, be transformed into solid after 24 hours.Leach this solid and drying in vacuum drier.
Embodiment 9
With 1g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide in the 10ml normal heptane, be heated to 60 ℃ 4 hours.Cooling mixture filters this solid and drying in vacuum drier to envrionment temperature then.
Embodiment 10
With 1g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide in the 10ml diisopropyl ether, be heated to 60 ℃ 4 hours.Cooling mixture filters this solid and drying in vacuum drier to envrionment temperature then.
Embodiment 11
With 10g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide in the 100ml diisopropyl ether, be heated to 60 ℃ 4 hours.Cooling mixture filters this solid and drying in vacuum drier to envrionment temperature then.
Embodiment 12
With 10g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide in the 1000ml normal heptane, be heated to 60 ℃ 4 hours.Cooling mixture filters this solid and drying in vacuum drier to envrionment temperature then.
Embodiment 13
At 50 ℃ with 10g 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide joins in the 30ml acetone.Cool off this solution then to envrionment temperature, add the 60ml normal heptane.Leach this solid and drying in vacuum drier.
Embodiment 15
With 50mg 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide is dissolved in 1mL acetone, tetrahydrofuran (THF) or the methyl ethyl ketone.This solution of of short duration heating is to guarantee dissolving.Add the 2.5mL diisopropyl ether to obtain crystalline solid in this solution at 25 ℃, it has the corresponding to x-ray diffraction pattern with embodiment 4 sample D.
Embodiment 16
With 50mg 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide is dissolved in 1mL acetone, tetrahydrofuran (THF) or the methyl ethyl ketone.This solution of of short duration heating is to guarantee dissolving.At 25 ℃ this solution is joined in the 2.5mL diisopropyl ether to obtain crystalline solid, it has the corresponding to x-ray diffraction pattern with embodiment 4 sample D.
Embodiment 17.2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide
With 2.25kg (1.00 equivalent) 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-N-(1-hydroxyl-suberyl-methyl)-benzamide, 0.780kg (1.5 equivalent) R-glycidyl methyl ether and 3.38kg silica gel (JT Baker Lot No.X46590) at 6.75L N, mix in the dinethylformamide, and are heated to 80 ℃.Cool off this reaction mixture, add 76.5L (68.1kg) ethyl acetate to be settled out silica gel, then with its filtering.Use saturated sodium bicarbonate (4.50kg/2.9L) washing ethyl acetate phase then, with remove residual 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-and N-(1-hydroxyl-suberyl-methyl)-benzamide, concentrate ethyl acetate layer then to smaller size smaller.From ethyl acetate mutually crystallization go out 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide and filtering separation.
The 2-chloro-N-of resulting separation (1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-sample of benzamide, and dry.As described in embodiment 4, measure residual solvent with the GC headspace analysis, obtain following residual solvent concentration through identifying.
| Methyl alcohol | Ethanol | Acetone | Ethyl acetate | Normal heptane | 2-methoxymethyl-oxyethane |
| - | - | 0.2％ | ＜0.01％ | 0.01％ | ＜0.01％-ND |
ND is not for detecting.
Claims (15)
1. method for preparing compound or its pharmacologically acceptable salts of general formula I,
R wherein
1Be (C
1-C
6) alkyl, optional by (C
3-C
8) cycloalkyl, phenyl, naphthyl, 5 or 6-unit's Heterocyclylalkyl or 5-or 6-unit heteroaryl replace each described (C wherein
1-C
6) alkyl, (C
3-C
8) cycloalkyl, phenyl, naphthyl, 5 or 6-unit's Heterocyclylalkyl or 5-or 6-unit heteroaryl is optional is independently selected from hydroxyl, halogen, CN-, (C by 1 to 3
1-C
6) alkyl, HO (C
1-C
6) alkyl, (C
1-C
6) alkyl-NH (C=O)-, NH
2(C=O)-, (C
1-C
6) alkoxyl group or (C
3-C
8) group of cycloalkyl replaces;
R
2Be hydrogen, halogen ,-CN or (C
1-C
6) alkyl, wherein said (C
1-C
6) alkyl optional by 1 to 3 be independently selected from halogen, hydroxyl, amino ,-CN, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-CF
3, CF
3O-, (C
1-C
6) alkyl-NH-, [(C
1-C
6) alkyl]
2-N-, (C
1-C
6) alkyl-S-, (C
1-C
6) alkyl-(S=O)-, (C
1-C
6) alkyl-(SO
2)-, (C
1-C
6) alkyl-O-(C=O)-, formyl radical, (C
1-C
6) alkyl-(C=O)-and (C
3-C
6) group of cycloalkyl replaces;
R wherein
4Be independently selected from
Hydrogen, halogen, hydroxyl ,-CN, HO-(C
1-C
6) alkyl, optional by the (C of 1-3 fluorine replacement
1-C
6) alkyl, optional by the (C of 1-3 fluorine replacement
1-C
6) alkoxyl group, HO
2C-, (C
1-C
6) alkyl-O-(C=O)-, R
5R
6N (O
2S)-, (C
1-C
6) alkyl-(O
2S)-NH-, (C
1-C
6) alkyl-O
2S-[(C
1-C
6) alkyl-N]-, R
5R
6N (C=O)-, R
5R
6N (CH
2)
m-, phenyl, naphthyl, (C
3-C
8) cycloalkyl, 5-or 6-unit heteroaryl, 5 or 6-unit Heterocyclylalkyl, phenyl-O-, naphthyl-O-, (C
3-C
8) cycloalkyl-O-, 5-or 6-unit's heteroaryloxy and 5 or Heterocyclylalkyl-the O-of 6-unit; With
R
7Be-CH
2-C (R
10R
11)-OH, wherein R
10And R
11Be independently selected from:
Hydrogen, phenyl and the optional (C that is replaced by 1-3 halogen
1-C
6) alkyl, hydroxyl ,-CN, (C
1-C
6) alkoxyl group-, ((C
1-C
6) alkyl)
n-N-, (C
1-C
6) alkyl-(C=O)-, (C
3-C
8) cycloalkyl-(C=O)-, 5 or 6-unit Heterocyclylalkyl-(C=O)-, phenyl-(C=O)-, naphthyl-(C=O)-, 5-or 6-unit heteroaryl-(C=O)-, (C
1-C
6) alkyl-(C=O) O-, (C
1-C
6) alkyl-O (C=O)-, (C
3-C
8) cycloalkyl, phenyl, naphthyl, 5 or 6-unit's Heterocyclylalkyl and 5-or 6-unit heteroaryl;
R
5And R
6Be selected from hydrogen, (C independently of one another
1-C
6) alkyl, HO-(C
2-C
6) alkyl and (C
3-C
8) cycloalkyl, perhaps R
5And R
6Can choose wantonly with nitrogen-atoms and link together formation 5 or 6-unit Heterocyclylalkyl;
N is 1 or 2; With
M is 1 or 2;
Wherein said method comprises the compound with general formula I I
Compound with general formula VIII
Reaction in the presence of at least a Lewis acid.
2. the process of claim 1 wherein that described Lewis acid is selected from
(a) boron trifluoride diethyl ether compound;
(b) Al
2O
3, Ti (O-Pr
i)
4, LiClO
4, or Zn (OAc)
2
(c) Eu (OTf)
3, Dy (OTf)
3, Ho (OTf)
3, Er (OTf)
3, Lu (OTf)
3, Yb (OTf)
3, Nd (OTf)
3, Gd (OTf)
3, Lu (OTf)
3, La (OTf)
3, Pr (OTf)
3, Tm (OTf)
3, Sc (OTf)
3, Sm (OTf)
3, AgOTf or Y (OTf)
3
(d) AlCl
3, AlI
3, AlF
3, AlBr
3, AsCl
3, AsI
3, AsF
3, AsBr
3, BCl
3, BBr
3, BI
3, BF
3, FeCl
3, FeBr
3, FeI
3, FeF
3, FeCl
2, FeBr
2, FeI
2, FeF
2, GaCl
3, GaI
3, GaF
3, GaBr
3, MgCl
2, MgI
2, MgF
2, MgBr
2, NbCl
5, SbCl
3, SbI
3, SbF
3, SbBr
3, SbCl
5, SbI
5, SbF
5, SbBr
5, SnCl
2, SnI
2, SnF
2, SnBr
2, SnCl
4, SnI
4, SnF
4, SnBr
4, TiBr
4, TiCl
2, TiCl
3, TiCl
4, TiF
3, TiF
4, TiI
4, ZnCl
2, ZnI
2, ZnF
2, or ZnBr
2
(e) BF
3BCl
3SMe
2, BI
3SMe
2, BF
3SMe
2, BBr
3SMe
2, BF
3OEt
2, Et
2AlCl, EtAlCl
2, MgCl
2OEt
2, MgI
2OEt
2, MgF
2OEt
2, MgBr
2OEt
2, Et
2AlCl, EtAlCl
2, or Zn (OAc)
2With
(f) (CH
3CO
2)
2Co, CoBr
2, CoCl
2, CoF
2, CoI
2, Co (NO
3)
2, trifluoromethanesulfonic acid cobalt (II), toluenesulphonic acids cobalt (II), (CH
3CO
2)
2Cu, CuBr
2, CuCl
2, CuF
2, CuI
2, Cu (NO
3)
2, copper trifluoromethanesulfcomposite (II), toluenesulphonic acids copper (II), (CH
3CO
2)
2Ni, NiBr
2, NiCl
2, NiF
2, NiI
2, Ni (NO
3)
2, trifluoromethanesulfonic acid nickel (II) or toluenesulphonic acids nickel (II).
3. the process of claim 1 wherein that described Lewis acid is a silica gel.
4. the method for claim 3, the compound of wherein said general formula VIII is (R)-(-)-glycidyl methyl ether.
5. the method for claim 3, the compound of wherein said general formula I I are 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-N-(1-hydroxyl-suberyl methyl)-benzamide.
6. the method for claim 3, the compound of wherein said general formula I is 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide.
7. the process of claim 1 wherein R
1Be (C
1-C
4) alkyl, optional by (C
3-C
8) cycloalkyl substituted; Wherein said (C
1-C
4) alkyl or (C
3-C
8) cycloalkyl is optional is independently selected from hydroxyl, halogen, CN-, (C by 1 to 3
1-C
6) alkyl, HO (C
1-C
6) alkyl, (C
1-C
6) alkyl-NH (C=O)-, NH
2(C=O)-, (C
1-C
6) alkoxyl group or (C
3-C
8) group of cycloalkyl replaces.
8. the method for claim 7, wherein R
2Be chlorine, methyl or ethyl.
9. the method for claim 8, wherein R
4Be hydrogen and R
7Be-CH
2-C (R
10R
11)-OH, wherein R
10And R
11Be independently selected from: hydrogen and optional by (C
1-C
6) alkoxyl group-or-(C that OH replaces
1-C
6) alkyl.
10. the method for claim 9, wherein R
4Be hydrogen and R
7Be selected from:
11. one kind prepares 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-method of benzamide, wherein said method comprises 2-chloro-5-(3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl)-N-(1-hydroxyl-suberyl methyl)-benzamide with (R)-(-)-the glycidyl methyl ether reacts in the presence of at least a Lewis acid.
12. a 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-composition of benzamide, comprise:
Crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide; With
Residual organic solvent less than 2.5%.
13. one kind prepares crystal 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 that contains less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-method for compositions of benzamide, comprising:
(a) with normal heptane with comprise 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-acetone soln of benzamide mixes, to produce 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3,5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal of benzamide; With
(b) separate 2-chloro-N-(1-hydroxyl-suberyl the methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 contain less than the residual organic solvent of 2.5% (w/w), 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-crystal of benzamide.
14. a treatment suffers from the patient's of disease method, wherein said disease is selected from rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, arthritic psoriasis, psoriasis, inflammatory diseases and autoimmune disorder, and this method comprises:
The administering therapeutic significant quantity contain crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide.
15. a pharmaceutical composition comprises:
The treatment significant quantity contain crystal 2-chloro-N-(1-hydroxyl-suberyl methyl)-5-[4-(2R-hydroxyl-3-methoxyl group-propyl group)-3 less than 2.5% residual organic solvent, 5-dioxy-4,5-dihydro-3H-[1,2,4] triazine-2-yl]-benzamide, itself and at least a pharmaceutically acceptable carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58381304P | 2004-06-29 | 2004-06-29 | |
| US60/583,813 | 2004-06-29 | ||
| US60/669,756 | 2005-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1976908A true CN1976908A (en) | 2007-06-06 |
Family
ID=38126301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800218405A Pending CN1976908A (en) | 2004-06-29 | 2005-06-17 | Method for preparing 5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]benzamide derivatives with P 2 X 7 inhibiting activity by reaction of the derivative unsubstituted in 4-positi |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1976908A (en) |
| ZA (1) | ZA200610421B (en) |
-
2005
- 2005-06-17 CN CNA2005800218405A patent/CN1976908A/en active Pending
-
2006
- 2006-12-12 ZA ZA200610421A patent/ZA200610421B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200610421B (en) | 2008-07-30 |
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